A Phase 3 interventional study of Clonidine and Morphine in Neonatal Abstinence Syndrome, sponsored by Henrietta Bada. Completed at 1 site in United States. Open to participants aged 12 Hours to 7 Days. Per ClinicalTrials.gov, last updated 2025-05-23.
Sponsored by Henrietta Bada · Phase 3, Interventional, and Treatment
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.
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
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
68 studies on the registry are indexed under Neonatal Abstinence Syndrome; 6 are open to participants now.
This study's enrollment of 120 is above the median of 48 across 52 interventional studies indexed under Neonatal Abstinence Syndrome.
Browse Neonatal Abstinence Syndrome studies →Henrietta Bada is the lead sponsor of 2 studies on the registry; none are open to participants now.
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Exclusion Criteria:
Babies randomized to clonidine will receive 1mcg/kg/dose (with a dosing interval of 3 or 4 hours).
Drug: Clonidine
Babies randomized to morphine will receive 0.06 mg/kg/dose (with a dosing interval of 3 or 4 hours).
Drug: Morphine
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
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
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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).
Time frame: 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)
Time frame: Once post discharge (between 18 months up to 24 months of age)
Duration of Treatment
Total number days of treatment
Time frame: 60 days
Childhood Behavior Checklist 1.5-5 T-Scores
On the CBCL 1.5-5, T-scores, with a mean of 50 and a standard deviation of 10, are used to interpret results, with scores of 65 or higher indicating a clinical range, and scores between 60 and 64 suggesting a borderline clinical range.
Time frame: Once post discharge (between 18 months up to 24 months of age)
| Milestone | Clonidine | Morphine |
|---|---|---|
| Started | 60 | 60 |
| Completed | 58 | 57 |
| Not completed | 2 | 3 |
| Withdrew: Physician decision | 2 | 3 |
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.
| score on a scale | Clonidine | Morphine |
|---|---|---|
| Habituation | 0.5 (-1.0 to 1.0) | 0.3 (-1.0 to 1.0) |
| Attention | 1.0 (-0.1 to 2.0) | 0.6 (0.2 to 1.6) |
| Handling | -0.1 (-0.4 to 0.1) | 0.1 (0.0 to 0.4) |
| Quality of movement | 0.1 (-0.3 to 0.8) | 0.0 (-0.5 to 0.5) |
| Regulation | 0.5 (-0.5 to 1.3) | -0.2 (-0.8 to 0.2) |
| Non-optimal reflexes | -1.0 (-2.5 to 1.0) | -1.0 (-2.0 to 1.0) |
| Asymmetry total/reflexes | 0.0 (0.0 to 0.0) | 0.0 (0.0 to 0.0) |
| Arousal | -0.1 (-0.6 to 0.3) | 0.4 (0.0 to 0.7) |
| Hypertonia | -1.0 (-2.0 to 0.0) | 0.0 (-1.0 to 0.0) |
| Hypotonia | 0.0 (0.0 to 0.5) | 0.0 (0.0 to 0.0) |
| Excitability | -1.0 (-3.0 to 1.0) | 1.0 (-1.0 to 3.0) |
| Lethargy | 0.0 (-0.1 to 0.0) | 0.0 (0.0 to 0.1) |
| Stress abstinence | 0.0 (-0.1 to 0.0) | 0.0 (0.0 to 0.1) |
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.
| score on a scale | Clonidine | Morphine |
|---|---|---|
| Cognitive | 113.0 ± 12.8 | 111.8 ± 11.1 |
| Language | 91.8 ± 13.4 | 87.7 ± 13.5 |
| Motor | 102.4 ± 16.4 | 97.4 ± 12.3 |
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.
| score on a scale | Clonidine | Morphine |
|---|---|---|
| Cognitive | 98.2 ± 11.5 | 97.2 ± 10.8 |
| Language | 91.8 ± 11.6 | 92.2 ± 12.2 |
| Motor | 99.1 ± 12.2 | 96.2 ± 9.3 |
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.
| score on a scale | Clonidine | Morphine |
|---|---|---|
| Cognitive | 84.3 ± 6.7 | 81.1 ± 9.6 |
| Language | 95.4 ± 9.4 | 86.2 ± 11.0 |
| Motor | 97.6 ± 7.2 | 96.0 ± 9.8 |
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).
| Participants | Clonidine | Morphine |
|---|---|---|
| Communication — Above cutoffs | 6 | 7 |
| Communication — Close to cutoffs | 0 | 3 |
| Communication — Below cutoffs | 1 | 0 |
| Gross motor — Above cutoffs | 7 | 10 |
| Gross motor — Close to cutoffs | 0 | 0 |
| Gross motor — Below cutoffs | 0 | 0 |
| Fine motor — Above cutoffs | 6 | 8 |
| Fine motor — Close to cutoffs | 1 | 2 |
| Fine motor — Below cutoffs | 0 | 0 |
| Problem solving — Above cutoffs | 4 | 9 |
| Problem solving — Close to cutoffs | 3 | 1 |
| Problem solving — Below cutoffs | 0 | 0 |
| Personal/social — Above cutoffs | 7 | 10 |
| Personal/social — Close to cutoffs | 0 | 0 |
| Personal/social — Below cutoffs | 0 | 0 |
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).
| Participants | Clonidine | Morphine |
|---|---|---|
| Communication — Above cutoffs | 8 | 8 |
| Communication — Close to cutoffs | 2 | 2 |
| Communication — Below cutoffs | 4 | 1 |
| Gross motor — Above cutoffs | 13 | 10 |
| Gross motor — Close to cutoffs | 1 | 1 |
| Gross motor — Below cutoffs | 0 | 0 |
| Fine motor — Above cutoffs | 8 | 8 |
| Fine motor — Close to cutoffs | 4 | 3 |
| Fine motor — Below cutoffs | 2 | 0 |
| Problem solving — Above cutoffs | 12 | 9 |
| Problem solving — Close to cutoffs | 2 | 2 |
| Problem solving — Below cutoffs | 0 | 0 |
| Personal/social — Above cutoffs | 12 | 10 |
| Personal/social — Close to cutoffs | 1 | 1 |
| Personal/social — Below cutoffs | 1 | 0 |
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)
| score on a scale | Clonidine | Morphine |
|---|---|---|
| Internalizing Problems | 52.31 ± 10.4 | 50.9 ± 13.9 |
| Externalizing Problems | 54.8 ± 13.4 | 53.5 ± 17.0 |
| Total Problems | 53.6 ± 12.6 | 53.5 ± 13.5 |
Total number days of treatment
| days | Clonidine | Morphine |
|---|---|---|
| Duration of Treatment | 17 (15 to 19) | 15 (13 to 17) |
On the CBCL 1.5-5, T-scores, with a mean of 50 and a standard deviation of 10, are used to interpret results, with scores of 65 or higher indicating a clinical range, and scores between 60 and 64 suggesting a borderline clinical range.
| Participants | Clonidine | Morphine |
|---|---|---|
| Internalizing Problems Borderline T-Scores | 5 | 2 |
| Internalizing Problems Clinical Range T-Scores | 1 | 8 |
| Externalizing Problems Borderline T-Scores | 2 | 2 |
| Externalizing Problems Clinical Range T-Scores | 3 | 6 |
| Total Problems Borderline T-Scores | 3 | 2 |
| Total Problems Clinical Range T-Scores | 1 | 8 |
Collected over Adverse events were collected from the time of consent until the subject was off study. For subjects who completed the entire study, the maximum amount of time for AE collection is 26 months from date of consent.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Clonidine | 1/60 (1.7%) | 9/60 (15%) | 52/60 (86.7%) |
| Morphine | 0/60 (0%) | 15/60 (25%) | 24/60 (40%) |
| Event | Clonidine | Morphine |
|---|---|---|
| Sustained tachycardiaCardiac disorders | 3/60 | 4/60 |
| BradycardiaCardiac disorders | 4/60 | 1/60 |
| Skin lesionsSkin and subcutaneous tissue disorders | 2/60 | 1/60 |
| HematocheziaGastrointestinal disorders | 2/60 | 2/60 |
| SeizureNervous system disorders | 0/60 | 2/60 |
| Respiratory Syncytial VirusInfections and infestations | 0/60 | 2/60 |
| Poor feedingGeneral disorders | 0/60 | 2/60 |
| Pyloric stenosisGastrointestinal disorders | 0/60 | 2/60 |
| Persistent ear infectionsEar and labyrinth disorders | 0/60 | 2/60 |
| HyperthermiaGeneral disorders | 0/60 | 1/60 |
| Event | Clonidine | Morphine |
|---|---|---|
| Finnegan scores consecutively >8Nervous system disorders | 24/60 | 17/60 |
| Phenobarbitol addedInvestigations | 15/60 | 5/60 |
| Adjunct medication addedInvestigations | 13/60 | 2/60 |
| Age, Categorical(Participants) | Clonidine | Morphine | Total |
|---|---|---|---|
| <=18 years | 60 | 60 | 120 |
| Between 18 and 65 years | 0 | 0 | 0 |
| >=65 years | 0 | 0 | 0 |
| Age, Continuous(weeks) | Clonidine | Morphine | Total |
|---|---|---|---|
| Mean | 38.7 ± 1.2 | 38.3 ± 1.3 | 38.4 ± 1.2 |
| Sex: Female, Male(Participants) | Clonidine | Morphine | Total |
|---|---|---|---|
| Female | 23 | 30 | 53 |
| Male | 37 | 30 | 67 |
| Ethnicity (NIH/OMB)(Participants) | Clonidine | Morphine | Total |
|---|---|---|---|
| Hispanic or Latino | 0 | 4 | 4 |
| Not Hispanic or Latino | 60 | 56 | 116 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Clonidine | Morphine | Total |
|---|---|---|---|
| American Indian or Alaska Native | 1 | 0 | 1 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 |
| White | 53 | 52 | 105 |
| More than one race | 6 | 8 | 14 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(participants) | Clonidine | Morphine | Total |
|---|---|---|---|
| United States | 60 | 60 | 120 |
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: No
Ran from Dec 2017 to primary completion in Apr 2024, 76 months.
Results were first posted in May 2025, 1 year 1 month after primary completion.
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Studies of the drugs tested here: Clonidine · Morphine
Neonatal Abstinence Syndrome →
Henrietta Bada