Clinical trial NCT03670160
Conditions: Neonatal Abstinence Syndrome
Sponsor: University of Tennessee Medical Center
Start date: 2018-10-01; Completion date: 2020-05-31
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare clonidine versus phenobarbital as adjunctive therapy in those infants who have failed monotherapy with morphine sulfate for neonatal abstinence syndrome (NAS).

Detailed description:

Arms: arm 1: Phenobarbital loading dose 20mg/kg in 2 divided doses, then 5 mg/kg/day divided every 12 hours. Phenobarbital continued throughout the infants hospitalization. arm 2: Clonidine 5 mcg/kg/day divided every 3 hours. Clonidine will be continued to achieve control of NAS symptoms. Clonidine may be weaned after successful discontinuation of oral morphine sulfate. Infants will not be discharged on clonidine.
Interventions: intervention 1: Phenobarbital intervention 2: Clonidine
Intervention descriptions: intervention 1: Phenobarbital loading dose 20 mg/kg in 2 divided doses, then 5 mg/kg/day divided every 12 hours. Phenobarbital dose will be adjusted to obtain desired trough of 25 to 30 mcg/mL. Levels will be obtained on Day 6 then weekly thereafter. Phenobarbital will be tapered over 4 weeks upon discharge from the hospital. The standardized taper is based the patient specific dose at the time of discharge. intervention 2: Clonidine 5 mcg/kg/day divided every 3 hours. Clonidine will be increased by 1.5 mcg/kg/day to achieve control of NAS symptoms based upon standardized scoring for neonatal abstinence syndrome. Clonidine will be weaned by 25% every 24 hours after successful discontinuation of oral morphine sulfate. Infants will not be discharged on clonidine.

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 6
Study Protocol
June 25, 2018
Revised March 3, 2020
Title
Clonidine versus Phenobarbital as Adjunctive Therapy 
Primary Investigators
Carrie Brusseau, PharmD and Tara Burnette, MD 
Research Support Staff
Robert Eric Heidel, PhD
Location 
University of Tennessee Medical Center
Objective
To compare clonidine versus phenobarbital as adjunctive therapy in those infants who 
have failed monotherapy with morphine sulfate for neonatal abstinence syndrome 
(NAS).
Background/Significance/Intervention to be studied
Neonatal abstinence syndrome (NAS) is the result of sudden discontinuation of 
substances used or abused by the mother during pregnancy after delivery6.  Opioids are 
the most common of these substances.  The signs and symptoms associated with NAS 
include disturbances in the gastrointestinal, autonomic and central nervous systems7.  
Up to 80% of infants will fail behavioral intervention and require pharmacologic 
treatment to control the symptoms associated with NAS6.  The American Academy of 
Pediatrics (AAP) supports the use of opioids as first-line pharmacotherapy for NAS6.    
Morphine sulfate is most commonly used in the United States for the treatment of NAS8.  
Despite appropriate treatment with opioids, many infants will often require adjunctive or 
second-line therapy.  Phenobarbital and clonidine are both considered as adjunctive 
therapy for the treatment of NAS.  Phenobarbital is considered the drug of choice for 
nonopiate withdrawal6 and is often used as adjunctive therapy in infants experiencing 
withdrawal due to maternal polysubstance abuse.  However, there are concerns about 
the long-term neurodevelopment and exposure to alcohol in infants who receive 
phenobarbital.  Studies have found clonidine to be an effective adjunctive therapy while 
a few recent studies have evaluated clonidine as initial therapy for the treatment of 
NAS2.    The limited data and concern for potential hypotension along with rebound 
hypertension may limit its use.  Studies have compared morphine sulfate versus 
clonidine as initial therapy2 and clonidine versus phenobarbital as in combination with 
morphine sulfate as initial therapy1. However, there are no current studies comparing 
clonidine and phenobarbital as adjunctive therapy in infants who have failed 
monotherapy with morphine sulfate for the treatment of NAS.  
IRB NUMBER: 4392
IRB APPROVAL DATE: 03/30/2020


Page 2 of 6
Study Endpoints
The primary endpoint of this study is the length of morphine sulfate therapy time from 
initiation of adjunctive therapy until hospital discharge in the two groups.  Secondary 
end points include time from initiation of adjunctive therapy until hospital discharge in 
the two groups, length of stay, length of morphine sulfate therapy, percentage of 
patients requiring triple therapy, safety and readmission rates.
Number of subjects
Approximately 50 patients will be enrolled in the study.
Inclusion / Exclusion Criteria
Inclusion Criteria 
Infants greater than or equal to 35 weeks admitted to the neonatal intensive care 
unit (NICU) who have failed monotherapy with morphine sulfate will be eligible for 
enrollment in the study.  Infants considered to have failed morphine sulfate 
therapy are those whose dose exceeds 0.15 mg (0.4 mL) q3h or have failed two 
attempts at weaning after initial stabilization.
Exclusion Criteria
Infants who develop NAS due to iatrogenic causes (analgesia or sedation), are 
unable to take oral medications at any point during their treatment or are in the 
custody of the department of child protective services with no legal guardian 
identified at the time of enrollment will be excluded.
Recruitment Methods
Subjects will be identified through medical record screening, contact with 
investigators patients in the clinical setting and referral from non-investigators 
(physicians, nurse practitioners or physician assistants).
Consent process
 An informed consent will be obtained from the parent or legal guardian for all 
infants enrolled in the study.
A notice of research will be provided with the admission documents to the 
parent/legal guardian of all infants being admitted for NAS.  If the patient fails 
monotherapy, the informed consent interview will be conducted and consent 
obtained over the phone.  The full signed consent will be left at the patient 
bedside and given to the parent/legal guardian at their next visit to the 
hospital.
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The informed consent interview will be conducted over the phone by study 
personnel if the legal guardian is not present at the time it is determined that 
an adjunctive agent is needed to control the study participants’ symptoms of 
NAS.  Documentation of consent by the legal guardian will be noted by the 
study investigator and a witness.  A copy of the informed consent will be left at 
the subject bedside to be provided to the legal guardian at the next visit to the 
NICU.
Methodology 
Study Design
This study will be a prospective, single-site, randomized, open-label study with 
institutional review board (IRB) approval.  The study will be conducted in the neonatal 
intensive care unit (NICU) at the University of Tennessee Medical Center.  
 
Study Treatment
Infants who have failed monotherapy with morphine sulfate and have documented 
informed consent will be randomized to receive phenobarbital (20 mg/kg load, then 5 
mg/kg/day divided q12h) or clonidine (6 mcg/kg/day divided q3h).  The phenobarbital 
and clonidine suspensions are 4 mg/mL and 10 mcg/mL, respectively.  Study agents will 
be titrated to achieve control of symptoms (previous 24-hour average FS less than or 
equal to 8).  The phenobarbital dose will be adjusted to obtain a desired trough of 25 to 
30 mcg/mL.  Levels will be obtained on Day 6, then weekly thereafter.  Infants with a 
trough less than 25 will receive an adjusted load of phenobarbital 1 mg/kg for every 1 
mcg/mL increase from obtained level to achieve a desired level of 25 mcg/mL and a 
change in the maintenance dose using a ratio of desired to measured phenobarbital 
level.  Clonidine will be escalated by 1.5 mcg/kg/day every 24 hours (maximum 12 
mcg/kg/day) to achieve control of symptoms.  Blood pressure (BP) is documented prior 
to each clonidine administration.  If hypotension occurs while receiving clonidine, the 
current dose will be held.  If more than 2 clonidine doses are held in the previous 24 
hours the total daily dose will be decreased by 1.5 mcg/kg/day.  After control of 
symptoms, morphine sulfate will be weaned by 0.02 mg (0.05 mL) every 24 hours as 
tolerated until off.  Morphine sulfate will be weaned if symptoms are controlled, and no 
rescue doses are required in the previous 24 hours.  A rescue dose of morphine sulfate 
0.02 mg (0.05 mL) may be given every 3 hours for consecutive FS greater than or equal 
to 11 while morphine sulfate is being weaned and after discontinuation.  Infants who 
experience return of symptoms and require more than 2 rescue doses in the preceding 
24 hours after discontinuing morphine will be placed back on the 0.02 mg (0.05 mL) 
until symptoms are controlled.  Once symptoms are again controlled, a second attempt 
to discontinue morphine sulfate will occur.  After morphine sulfate has been 
discontinued for 24 hours and symptoms are still controlled, the study agent can be 
weaned.  Clonidine will be weaned by 25% (based on the dose at time of morphine 
sulfate discontinuation) every 24 hours over 72 hours. Infants will be observed for return 
of symptoms and rebound hypertension for 48 hours prior to discharge.  Blood pressure 
will be measured every shift for 48 hours after discontinuation of clonidine.  Infants who 
experience rebound hypertension or fail to maintain control of symptoms after 
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IRB APPROVAL DATE: 03/30/2020


Page 4 of 6
discontinuation of clonidine will be placed back on the last effective dose until symptoms 
are controlled.  Once symptoms are controlled, weaning will resume. Infants receiving 
phenobarbital will also be observed for 48 hours after the discontinuation of morphine 
sulfate prior to discharge.  Phenobarbital will be weaned as an outpatient based on the 
standard taper used in the NICU for over 5 years (Table 1).  
Table 1:  Standard phenobarbital taper based on dose at discharge
Phenobarbital dose on day 
of discharge
Standardized phenobarbital taper initiated upon 
discharge
5.1 to 7 mg every 12 hours
6 mg two times a day for 1 week, then 4 mg two times a 
day for 1 week, then 2 mg two times a day for 1 week, 
then 2 mg once a day for 1 week, then stop
7.1 to 9 mg every 12 hours
8 mg two times a day for 1 week, then 6 mg two times a 
day for 1 week, then 4 mg two times a day for 1 week, 
then 2 mg two times a day for 1 week, then stop
9.1 to 11 mg every 12 hours
10 mg two times a day for 1 week, then 8 mg two times 
a day for 1 week, then 4 mg two times a day for 1 
week, then 2 mg two times a day for 1 week, then stop
11.1 to 13 mg every 12 
hours
12 mg two times a day for 1 week, then 8 mg two times 
a day for 1 week, then 6 mg two times a day for 1 
week, then 2 mg two times a day for 1 week, then stop
13.1 to 15 mg every 12 
hours
14 mg two times a day for 1 week, then 10 mg two 
times a day for 1 week, then 6 mg two times a day for 1 
week, then 4 mg two times a day for 1 week, then stop
If symptoms are unable to be controlled with the study agent alone, the addition 
of the nonrandomized medication (phenobarbital/clonidine) may be initiated to 
control symptoms.  Morphine, clonidine and phenobarbital, in that order, will be 
weaned per protocol.  
The patient medical record will be reviewed to collect data about the subjects.  
This includes the patient’s electronic medical record and chart.
Risks to subjects
Risks to participants include side effects associated with study medication, potential 
increased length of stay/treatment compared to those patients receiving comparative 
medication and loss of confidentiality.  Both of the study medications are commonly 
used in this patient population and considered standard of care with no evidence of 
superiority in the treatment of NAS.  
Benefits to subjects 
It is not known if one of the study medications will better control withdrawal symptoms, 
allow us to wean oral morphine faster, have fewer side effects or allow the infant to be 
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IRB APPROVAL DATE: 03/30/2020


Page 5 of 6
discharged from the hospital sooner.  The knowledge gained from this research will help 
us determine if clonidine or phenobarbital could better control symptoms of withdrawal, 
have less side effects or allow children to be discharged from the hospital sooner.
Data Management 

The primary endpoint of time from initiation of adjunctive therapy until hospital 
discharge will be assessed using Mann-Whitney U test.  Secondary 
Endpoints of length of stay and length of morphine therapy will also be 
assessed via Mann-Whitney U test.  Side effects and readmission rate via 
chi-squared with an unadjusted odds ratio with 95% CI for 30-day 
readmission.  

A power analysis was completed for sample size (based on Surran et al 
findings with power to detect a 5-day difference in treatment time):
 
It is predicted that a sample size of 25 in each treatment group will be 
powered to detect 1.2-day difference in time from initiation of adjunctive 
therapy until hospital discharge. 

All paper research records containing data from individual subjects will be 
locked and stored.  All electronic research records containing data from 
individual subjects will be computer password protected.  All records will be 
accessible only to research personnel.
Withdrawal of Subjects 
Subjects may withdraw their permission for participation in research at any time.  Subjects 
will contact Dr. Carrie Brusseau in writing to let us know they are withdrawing their 
permission.  The mailing address is 1924 Alcoa Highway, U-41, Knoxville, TN 37920.  
At that time, we will stop further collection of any information.  However, the health 
information collected before this withdrawal may continue to be used for the purposes of 
reporting and research quality.
IRB NUMBER: 4392
IRB APPROVAL DATE: 03/30/2020


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References
1.
Surran B, Visintainer P, Chamberlain S, Kopcza K, Shah B and Singh R.  Efficacy of 
clonidine versus phenobarbital in reducing neonatal morphine sulfate therapy days for 
neonatal abstinence syndrome.  A prospective randomized clinical trial.  Journal of 
Perinatology. 2013; 22:954-959.  
2.
Bada H, Sithisarn T, Gibson J, Garlitz K, Caldwell R, Capilouto G, Li Y, Leggas M and 
Breheny P.  Morphine versus clonidine for neonatal abstinence syndrome.  Pediatrics. 2015; 
135(2): e383-e391.
3.
Coyle M, Ferguson A, Lagasse L, Oh W and Lester B.  Diluted tincture of opium (DTO) and 
phenobarbital versus DTO alone for neonatal opiate withdrawal in term infants.  The Journal 
of Pediatrics.  2002; 5:561-564. 
4.
Hudak ML, Tan RC.  Neonatal drug withdrawal.  Pediatrics. 2012:129(2):e540-e560.
5.
McQueen K and Murphy-Oikonen J.  Neonatal Abstinence Syndrome.  N Engl J Med.  375; 
25:2468-2479.
6.
Kocherlokata P.  Neonatal Abstinence Syndrome.  Pediatrics.  2014;134(2):e547-e561 
7.
Opioid abuse, dependence, and addiction in pregnancy.  Committee Opinion No. 524.  
American College of Obstetricians and Gynecologists.  Obstet Gynecol 2012; 119:1070-6
8.
Stover MW, Davis JM. Opioids in pregnancy and neonatal abstinence syndrome.  Semin 
Perinatol. 2015;39:561-565.
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Streetz V, Gildon B and Thompson D.  Role of clonidine in neonatal abstinence syndrome.  
A systemic review.  Annals of Pharmacotherapy.  2016;50(4)301-310.
IRB NUMBER: 4392
IRB APPROVAL DATE: 03/30/2020