Final Protocol Approved
PROTOCOL
Comparison of Clonidine versus Phenobarbital as an Adjunct Therapy for Neonatal
Abstinence Syndrome.
Hypothesis:
Infants being treated for neonatal abstinence syndrome with a combination of Clonidine
and neonatal morphine sulfate will have a shorter length of treatment in comparison to a
combination of phenobarbital and neonatal morphine sulfate.
Background and Aims:
Neonatal abstinence syndrome (NAS) is a symptom complex experienced by 55 to 94%
of neonates who are exposed to intrauterine opioids (1-6). Clinical features of NAS
involve multiple systems with predominance of neurological symptoms which include
hyperexcitability, insomnia, irritability, hypertonia, hyperreflexia, tremors, and seizures.
Other features include enteric symptoms (vomiting, diarrhea, feeding disturbances), and
sympathetic and parasympathetic dysregulation including sweating, fever, tachypnea, and
congestion. (7)
A greater awareness of maternal opioid addiction (heroin and cocaine) has lead to
substitute therapies with methadone and buprenorphine (Subutex) ( 8-14). Currently
NAS is seen secondary to maternal polydrug usage and hence the pharmacologic therapy
for NAS needs greater attention. Pharmacotherapy in the neonatal period is based upon
the Finnegan scoring system and usually initiated when consecutive scores are ≥ 8.
Recent studies have shown that combination therapies are superior to monotherapy with
neonatal morphine sulfate (NMS). Phenobarbital, a barbiturate and
anticonvulsant/sedative, has been shown to reduce the length of hospitalization, decrease
severity of withdrawal, as well as decrease hospital costs and care giver demands (15-17).
Adjunct therapy with clonidine, an α2-adrenergic receptor agonist, is safe, effective and
reduces length of treatment when compared to treatment with opioid and placebo (18-22).
Phenobarbital is an antiepileptic with action on GABA(A) receptors and has been shown
in animal models to inhibit neuronal cell proliferation, survival, and neurogenesis (23). In
human infants long term treatment with Phenobarbital may result in neuro-developmental
compromise (24) Due to these potential harmful effects of phenobarbital alternative
therapies should be explored more thoroughly including clonidine.
Specific Aims: To examine whether the duration of neonatal morphine sulfate (NMS)
treatment is reduced when accompanied by clonidine (NMS_C, experimental group) vs
Phenobarbital (NMS-P, standard). Secondary outcomes include length of stay for NAS,
treatment failures, and adverse events (bradycardia, hypo- and hypertension).
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We hypothesize that clonidine when compared to phenobarbital as an adjunct therapy,
will have shorter length of stay, with fewer treatment failures and side effects.
Methods:
This study will be a prospective, randomized, non-blinded clinical trial of neonatal
morphine sulfate and clonidine (NMS/C) versus NMS and phenobarbital (NMS/P).
Infants will be recruited from the Baystate Children’s Hospital Neonatal Intensive Care
Unit (NICU) and Neonatal Continuing Care Nursery (NCCN) after IRB approval has
been obtained for the study. A written informed consent will be obtained from the
parents. Since Department of Children and Family Services (DCF) is always notified
secondary to maternal drug usage, if DCF has custody of the infant then the consent will
be obtained from the DCF case worker assigned to the case.
Infants meeting the following criteria will be eligible for this study:
Inclusion criteria:
 0 to 15 days of age
 Prenatal exposure to opioids with development of moderate to severe NAS (2
consecutive abstinence scores of ≥ 8)
 Medically stable
Exclusion criteria:
 Gestational age < 35 weeks
 Infants withdrawing from maternal use of benzodiazepines
 Intrauterine growth retardation (birth weight below the 5th percentile)
 Congenital heart disease
 Congenital anomalies
 Medically unstable
Study Groups:
Two groups will be compared in this trial. The experimental therapeutic approach
– NMS with clonidine—will be compared to the standard therapeutic approach—NMS
with phenobarbital.
a) New treatment group (NMS-C):
Initiation of therapy for patients randomized to the NMS-C group will follow the
schedule below:
Finnegan Score NMS
mg/kg/day divided q3hr
8-10
0.32
11-13
0.48
14-16
0.64
≥ 17
0.80
Clonidine
mcg/kg/day divided q6hr
6
8
10
12
2
* If needing NMS > 0.80 mg/k/day then increase dose in increments of 0.16
mg/kg/day till Finnegan score <8
+ Clonidine escalation may be limited by hypotension or bradycardia
b) Standard treatment group (NMS-P):
Treatment management of patients receiving standard therapy is described below.
Finnegan Score NMS
Phenobarbital
mg/kg/day divided q3hr mg/kg/day divided q8hr
8-10
0.32
6
11-13
0.48
8
14-16
0.64
10
≥ 17
0.80
12
* If needing NMS > 0.80 mg/k/day then increase dose in increments of 0.16 mg/kg/day
till Finnegan score <8
Clinical Care of Study Participants
Once enrolled in the study infants will have their daily care as per the pre-existing NICU
and NCCN protocols for vital signs and other clinical parameters required for daily care.
Infants in the Clonidine group will be initially admitted to the NICU for 24hrs to ensure
stable blood pressures before transitioning to the NCCN. Since blood pressure monitoring
is not a routine in the NCCN, infants in the study will have their blood pressures
monitored every 6hrs for the first 48hrs after starting and stopping the protocol, in
between they will get twice daily blood pressure monitoring at 12h intervals, in addition
to the other routine standard vital signs.
In addition, all infants will have Finnegan scores documented q3h. Since enrollment in
the study will mean that the infant is undergoing NAS, based on their randomization , the
infants will be started on NMS and additional therapy with clonidine 6 -12 mcg/kg/day
divided every 6 hours or Phenobarbital 6 -12 mg/kg/day divided every 8 hours, with
starting dosage based on initial abstinence score.
The NMS solution used will be 0.4 mg/ml as per the current protocol used in the NICU
based on the Finnegan scores to guide escalation and de-escalation of morphine.
The Clonidine solution used will be 10 mcg/ml and the protocol used will be based on
Finnegan scores and studies published by Holder et al and Agthe et al. If after initiation
of Clonidine, bradycardia and/or hypotension are noted the dose will be decreased to the
next lower dose until the vital signs stabilize.
Study withdrawal criteria: Infants with persistent side effects of bardycardia and/or
hypotension not responding to dose adjustments will be eligible for withdrawal from the
protocol. Most adverse effects are mild and tend to diminish with continued therapy. The
most frequent side effects reported in pediatric and adult population (which appear to be
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dose-related) are dry mouth, occurring in about 40 of 100 patients; drowsiness, about 33
in 100; dizziness, about 16 in 100; constipation and sedation, each about 10 in 100. The
cardiovascular side effects are bradycardia and hypotension are usually mild responding
to dose adjustments. Severe side effects such as AV block are rare (i.e.1 in 100) and seen
when subjects received concomitant therapies with Clonidine such as beta blockers or
methylphenidate.
Weaning Protocol. Infants will be maintained on original pharmacotherapy for 48 hours
following initiation. Each infant will have morphine sulfate reduced by 10% of absolute
dose if abstinence scores remain ≤ 8 for 24 hours. Each infant will be eligible to be
weaned in this step-wise fashion once in a 24 hour period. If an infant develops
recurrence of withdrawal symptoms with abstinence scores > 8 x 2 or more over a 24
hour period following a wean will be on hold, if scores significantly higher persistently
(>10 x 2) then the morphine dosage will be escalated to the last effective dose.
Infants will be continued on clonidine at the last effective dose until the morphine sulfate
is weaned off in order to prevent recurrence of symptoms of NAS. After morphine wean
has been completed, clonidine will be weaned by 50% in a two step reduction (every 24
hours) until off. The stepwise wean of clonidine will be undertaken in order to prevent
the occurrence of rebound hypertension and sympathetic overactivity; two adverse effects
that have been observed with abrupt discontinuation of clonidine (18)
Starting
Clonidine Daily
Dose
6 mcg/kg/day
8 mcg/kg/day
10 mcg/kg/day
12 mcg/kg/day
First clonidine weaning
dose
Second clonidine weaning
dose
Third weaning step
3 mcg/kg/day x 24 hours
4 mcg/kg/day x 24 hours
5 mcg/kg/day x 24 hours
6 mcg/kg/day x 24 hours
1.5 mcg/kg/dose x 24 hours
2 mcg/kg/day x 24 hours
2.5 mcg/kg/day x 24 hours
3 mcg/kg/day x 24 hours
Discontinue clonidine
Discontinue clonidine
Discontinue clonidine
Discontinue clonidine
Phenobarbital is not weaned during the hospital stay and infants are discharged home on
it per current unit protocol.
Infants will be observed for 36-48 hours off Clonidine prior to discharge home.
Randomization Scheme
Infants who meet the inclusion criteria, after informed consent from the parents or
guardians will be randomly assigned to one of the study groups- either NMS-C or NMSP. Patients will be randomized to groups under equal allocation according to a computer
generated randomization procedure. Patients will be randomized in blocks sizes of 4 and
6. Block randomization will insure that study groups will remain balanced at the
completion of each block and that unbalanced study groups is minimized if the study is
terminated during a block interval.
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To insure that study groups are balanced on important patient characteristics,
randomization will be stratified by type of maternal drug use: Methadone/ buprenorphine
(Subutex) versus Polydrug use.
Primary Outcome Measures
The primary outcome will be length of treatment with NMS in the two study
arms. It will be defined as the total number of days the infants were on NMS before
successfully weaning off of it completely. Phenobarbital is not weaned during the
hospital stay and infants are discharged home on it hence time to wean off of NMS is a
more appropriate measure of treatment efficacy.
Secondary Outcome Measures
a)
b)
c)
d)
Our secondary outcomes will be
Total length of hospital stay for NAS treatment. It will be defined as total number
of days the infant was in the hospital while on pharmacotherpeutic agents for
NAS treatment. Occasionally infants will stay hospitalized for non-medical
reasons increasing the hospital stay.
The mean total treatment dose and mean daily dose of NMS required in the two
study arms will be recorded
Total number of treatment failures: Will be defined as the number of times that
the infant failed a wean and had to be escalated to the previous dose
Adverse effects:
1) Bradycardia will be defined as sustained HR <80 beats/minute
2) Hypotension will be defined as mean blood pressure <2 SD for the infants
gestational age (Mean BP = Mean GA)
3) Hypertension will be defined as mean blood pressure > 2 SD for the
infants gestational age (Mean BP = Mean GA)
Data Collection:
Maternal data would include detailed drug history during the pregnancy (drug and
dosages), urine toxicology, concomitant alcohol and smoking history.
Infant data will include gestational age, birth weight, Apgar score at 5 minutes, baseline
heart rate and blood pressure at admission, then every 6h for 48h followed by every 12
hours after initiation of the protocol, and 24 and 48hours after discontinuation of therapy,
type of feedings (formula versus breast milk). If formula is the preferred by mothers than
all infants in the study will be on a soy formula. All infants will have daily vital signs
monitoring as per the current NICU/NCCN policy. In addition infants in the NCCN will
have blood pressures recorded daily at 12h interval.
Specific data will also be collected on each infant including:
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



Amount of NMS necessary to control symptoms
Duration of NMS therapy
Duration of hospitalization for NAS treatment
Treatment failure
Sample Size Estimation
Sample size and statistical power were estimated using PASS (J. Hintze, PASS
ver. 8.0.7, 2008, Kaysville, UT). The current mean duration of treatment for NAS at the
Baystate Children’s hospital is 25.8 days. A 20% reduction in the duration of treatment
(i.e., approximately 5 days) is considered clinically meaningful. Assuming a common
standard deviation of approximately 8.5 days (based on our clinical data), a sample size
of 55 infants per group (total of 110 patients) would provide more than 80% power for a
2-tailed test of significance at a critical value of 5%.
In the event that survival analysis is used, a sample size of 55 infants per group
would provide about 80% power to detect a 40% reduction in time-to-weaning from
NMS, assuming a two-sided test of significance at a critical level of 5%. This hazard
ratio is equivalent to a reduction in the median time-to-weaning from 26 days to 15 days.
This analysis assumes that approximately 5% of infants will be of infants will be
censored by the end of follow-up. Our clinical experience indicates that there will be
little or no censoring.
Data analysis
Treatment and control groups will be compared on baseline characteristics to
identify patient or clinical factors that may not have been adequately balanced by the
randomization procedure. Continuous variables will be compared using 2-sample t-tests
or its non-parametric equivalent (Wilcoxon rank-sum test), while categorical variables
will be compared using Pearson chi-square or Fisher’s exact test. Differences on baseline
characteristics achieving a p-value of .15 or less will be included in subsequent
multivariable analysis. For analyses using the survival approach, bivariable analyses will
be based on the Kaplan-Meier product-moment estimator. Statistical testing will used the
log-rank test.
Multivariable analyses will be conducted using two approaches. First, if data on
time-to-weaning are not skewed and there is no censoring, linear regression will be used.
The primary outcome will be the length of treatment with NMS in the two study arms,
defined as the mean number of days the infants were on NMS before successfully
weaning off of NMS completely. Independent variables will include the dichotomous
variable representing study group, as well as baseline characteristics requiring
adjustment. If time data are highly skewed, the time data will be log transformed and
linear procedures will be applied.
Secondly, we will use survival analytic approaches ( Cox proportional hazard
regression) to compare the study groups, particularly in the event that there is censoring
(e.g., due to transfers or withdrawals from the study). Proportional hazards regression
will be used to control for baseline variables requiring adjustment despite randomization.
Survival models will be developed and model assumptions will be verified using methods
described by Hosmer and Lemeshow (1999).
All subjects will be analyzed on an intention-to-treat basis.
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Early Termination of Study
To determine whether early termination of the trial is necessary due to larger than expect
benefit or larger than expected harm, we plan one interim look at the data when 50% of
the patients have completed follow-up. We will use the Obrien-Fleming (1979) spending
function to adjust the alpha comparison at the interim analysis and the final analysis in
order to maintain an overall critical level of 5% (overall p-value is 5%). Thus, the trial
will be terminated early if at the interim analysis the absolute difference in the proportion
of A-V block between the study groups achieves a significance level of p ≤ 0.003. For
the final analysis at study completion, significance testing will be conducted at p ≤ 0.047.
This adjustment ensures that the comparisons will be conducted at an overall significance
level of 5%.
Data Storage and Confidentiality:
1. Certificate of Confidentiality: All maternal and infant data will be recorded from
the infant’s medical record and de-identified, hence the information collected will
not pose any adverse consequences for subjects or damage their financial
standing, employability, insurability, or reputation. A certificate of confidentiality
is thus not needed.
2. Each infant will be given a study number allocated to them, which will be linked
to the infant’s medical record number. The key to the study number will be stored
by the PI on her personal office computer. No one other than the PI will have
access to the key, ensuring maintenance of confidentiality.
3. The PI will be the only one with access to the key to the identity code. The deidentified infant data will be accessible to Dr. Brooke Surran, Dr. Bhavesh Shah,
Dr. Paul Visintainer, Ms. Susan Chamberlain and Ms. Kathleen Kopcza.
4. No data will be moved/shared outside of Baystate Medical Center. If presenting
the analyzed data for research meetings or publication, then only the de-identified
data will be presented.
Risks and benefits:
Multiple studies have shown clonidine used in the above mentioned doses to have
relatively few side effects with the main one being hypotension at the initiation and
rebound hypertension with abrupt weaning.
If at any time any study modification to therapy is not tolerated by the infant
(bradycardia, seizures, hypoxia, hypo or hypertension for age and condition), the infant
will be assessed and returned to previous dosages for stabilization.
This comparison study is potentially of great significance. If clonidine is proven to be
equally effective in treatment of NAS many of the detrimental effects of phenobarbital
therapy may be avoided for infants on long term pharmacotherapy for treatment of
withdrawal with shorter length of hospital stay.
References:
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intensive care units: a national survey. J Perinatol 2006;26(1):15–17.
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(DTO) and Phenobarbital versus DTO alone for neonatal opiate withdrawal in term
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Interim Analysis Report
An interim analysis was planned about midway through enrollment to examine whether
significant clinical or statistical differences in adverse events emerged between the
groups. This report summarizes the findings of the interim analysis. Two principal
results emerged from analysis: a) No clinically important or statistically significant
differences were found between the study groups [Phenobarbital (i.e., standard of care)
vs. Clonidine), b) a futility analysis indicated extremely low conditional power for
finding the hypothesized difference. As such, we recommend that the trial be terminated.
Adverse Events. At the interim analysis, there were 32 patients assigned to the
Phenobarbital group (i.e., standard of care group) and 28 patients assigned to the
Clonidine group. Only two adverse events were recorded among the 60 study patients,
both occurring in the Phenobarbital group (i.e., the standard of care group). The two
cases represent an event rate in the Phenobarbital group of 4.2 events per 1000 tx-days
(95% CI: 0.5 events per 1000 tx-days to 15.2 events per 1000 tx-days). In the Clonidine
group, although no adverse events were observed, an event rate of 5.2 events per 1000 txdays is possible, as indicated by the upper 95% CI. The difference in event rates between
the two groups in the adverse event rate did not achieve statistical significance (p = 0.16).
Further, the event rate in the Phenobarbital group was not considered to be clinically
unusual by the PI.
Futility Analysis. Prior to beginning the study, we hypothesized that patients in the
Clonidine group would achieve an average of five fewer days on neonatal morphine
sulfate (NMS) (our primary outcome) compared with the Phenobarbital group (i.e., mean
difference = 5 days; pooled SD = 8.5 days). The projected sample of 55 patients per
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group would provide more than 80% power to detect this difference as significant,
assuming no attrition.
At the interim analysis, a univariable comparison of the groups on the NMS days showed
the following results. (We note that for this analysis we excluded two patients who were
withdrawn from the study early due to treatment failure – not adverse events – and
received Phenobarbital as the standard of care.)
Statistic
Phenobarbital (UC)
Clonidine
Mean
12.19 days
17.57 days
SD
6.02 days
9.07 days
n
32
28
The observed difference in the means of -5.38 days between the groups was significant at
p = 0.008. Furthermore, the difference was in the opposite direction than originally
hypothesized. That is, we hypothesized that patients receiving Clonidine would average
fewer NMS days relative to patients receiving Phenobarbital. However, we found the
reverse to be true.
In view of this observed reversal in outcome, we conducted a futility analysis according
to Proschan et al (2010) to determine the likelihood of achieving the hypothesized result
given the data at the interim analysis. Thus, the conditional power based on the observed
data at the interim analysis is: CP3.09(0.55) < 0.01. [The values 3.09 refer to the drift
parameter hypothesized at the start of the study and 0.55 refers to the information fraction
at the interim analysis.] That is, given the results of the interim analysis, the probability
of detecting the hypothesized difference if it is true is less than 1% (as compared to 80%
power at the start of the study). Proschan et al (2010) note that conditional power of less
than 0.15 is commonly used for study curtailment. Based on this result, we recommend
suspending further enrollment into the study.
We plan to keep the study open in order to complete data analysis. We plan to conduct a
full analysis of the trial and submit our findings for publication.
Reference:
Proschan MA, Lan GK, Wittes JT. Statistical Monitoring of Clinical Trials. New York:
Springer; 2010.
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