Clinical trial NCT03608696
Conditions: Neonatal Abstinence Syndrome Neonatal Opiate Withdrawal Syndrome
Keywords: buprenorphine pharmacometrics
Sponsor: Thomas Jefferson University
Start date: 2018-08-29; Completion date: 2019-07-11
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Neonatal withdrawal syndrome is a series of signs and symptoms in infants exposed to opioids in utero. Buprenorphine has demonstrated a 40% reduction in length of pharmacologic treatment compared to oral morphine. These results were with an empirically derived dose. This study will use pharmacokinetic modeling-informed dosing to clarify the dose/response relationship and use a rational approach to define an optimal dose regimen. The clinical trial will be open label, single arm design with a goal of initial testing of a new dosing regimen.

Detailed description:
The overall rationale for this study is to explore new dose regimens in a small number of patients. There is evidence from pharmacometric models with dose simulation that suggest there is room for improvement in buprenorphine dosing. This study will explore these doses. While the endpoint will be primarily pharmacokinetic, it is likely that the revised dose regimen will be more effective and thus holds the potential for benefit for those infants participating. This information will be used to feed back to the model and generate rationally derived, optimal doses to be tested in subsequent efficacy trials.

The neonatal abstinence syndrome (NAS) is a set of signs of withdrawal in an infant with in utero exposure to opioids. Cardinal manifestations include increased muscle tone, autonomic instability, irritability, poor sucking reflex, gastrointestinal symptoms, and impaired weight gain. All infants are treated with non-pharmacologic methods such as swaddling, rooming in with mother and minimization of stimuli. Despite these measures, \~50% of infants require pharmacologic treatment to ensure proper growth and development. While the optimal pharmacologic treatment for NAS has not been identified, expert review identifies an opioid as the primary therapy. In the US 80% of infants are treated with morphine and 20% with methadone. Sublingual buprenorphine has been demonstrated to be safe and effective in an open label phase 1 clinical trial conducted by the Thomas Jefferson University Team \[NCT00521248\]. These data were used to plan the BBORN (Blinded Buprenorphine OR Neonatal morphine solution) clinical trial \[NCT01452789\] comparing buprenorphine to morphine for NAS. BBORN demonstrated a 40% reduction in length of treatment compared to morphine in a double blind fashion (New England Journal of Medicine, June 2017). The external validity of this finding has been supported by retrospective examination of buprenorphine used in a treatment paradigm at the University of Cincinnati Medical Center, with a reduction in length of treatment of \~30% in \>200 infants.

Dose selection for both the phase 1 trial and the efficacy trial (BBORN) were empirically derived. A population pharmacokinetic model for buprenorphine in NAS has been published by our group. In addition a pre-specified endpoint for the BBORN trial was a pharmacokinetic analysis of buprenorphine. A pharmacokinetic/pharmacodynamic model from the BBORN study has been published (Clinical Pharmacology and Therapeutics, March 2018). The time to control of symptoms was directly tied to buprenorphine exposure, which itself appeared to be driven primarily by clearance. Among the strengths of pharmacometric models is the ability to simulate in silico many potential dose regimens. In this manner, a dose regimen can be chosen that is more likely to be in the desired range of concentrations. This approach also allows for incorporation of covariates of drug exposure or response to treatment. This is much safer and efficient than the traditional approach of choosing an empiric dose that would need to be tested in clinical trial. An ideal dose would quickly reach this exposure while maintaining a good safety margin. There was no evidence of decline in respiratory rate in infants treated with higher doses of buprenorphine compared to lower doses, or those treated with buprenorphine compared to those treated with morphine. This may allow a higher initial dose to more quickly reach therapeutic buprenorphine concentrations. This ultimately could lead to shorter lengths of treatment and stay, though achieving this goal is outside of the scope of the current proposed project.

In summary, buprenorphine at the dose and schedule used in prior clinical trials has been demonstrated to be safe and effective. The goal of the proposed study is to simulate a dose of sublingual buprenorphine for NAS using pharmacometric modelling techniques. This dose will be tested in infants requiring treatment for NAS. Pharmacokinetic samples would be collected and used to confirm and refine the pharmacokinetic model. The proposed study would allow broad examination and refinement of the exposure/response relationship. This optimized dose could later be used in an efficacy trial.

Arms: arm 1: Buprenorphine 0.075 mg ml sublingual solution

Initial daily dose 24 mcg/kg/day Initial unit dose 8 mcg/kg q8 hours Maximum daily dose 75 mcg/kg/day Maximum unit dose 25 mcg/kg q8 hours Up-titration rate 33% Maximum # of up-titrations 4 Weaning rate 15% Cessation (bottom) dose \< Initial dose Dosing interval until bottom dose (hrs) 8 Dose interval extension #1 at bottom dose (hrs) 12 Dose interval extension #2 at bottom dose (hrs) 24
Interventions: intervention 1: Buprenorphine
Intervention descriptions: intervention 1: buprenorphine 0.075 mg/ml solution

Protocol documents:
Prot_000.pdf: 
Version 1.1 
 
1 
Title 
Modeled Dose Exposure of Sublingual Buprenorphine in the 
Neonatal Opioid Abstinence Syndrome 
 
Short Title 
B-PHORE   
(Buprenorphine Pharmacometric Open Label Research study 
of Drug Exposure) 
 
 
Clinical Study Site 
Thomas Jefferson University Hospital 
Philadelphia, PA 
 
Principal 
Investigator 
Walter K. Kraft, MD 
Department of Pharmacology and Experimental Therapeutics 
1170 Main Building 
132 S. 10th St 
Philadelphia, PA 19107 
 
Co-Investigators 
Susan Adeniyi-Jones, MD 
Denis Hand, PhD 
 
 
 
Analytic Chemistry 
University of Utah 
David Moody, PhD 
 
Pharmacometrics 
Children’s Hospital of Philadelphia 
Nicole Zane, PharmD, PhD 
Athena Zuppa, MD 
 
 
Pharmacogenetics 
Mt. Sinai School of Medicine 
Michelle E. Ehrlich, MD 
 
Protocol Date 
April 27, 2018 
 
IND 
68,403 
 
Institutional 
Review Board 
Thomas Jefferson University 
 
 
Version 
1.1 
 


Modeled Dose Exposure of Sublingual Buprenorphine in the Neonatal Opioid Abstinence Syndrome 
 
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2 
PROTOCOL SYNOPSIS 
Primary 
Objective 
To define buprenorphine pharmacokinetic exposure in infants treated with 
buprenorphine for neonatal abstinence syndrome (NAS) using a model-
based optimized dose. 
 
Exploratory 
Objectives 
To examine the safety of a model-based optimized dose of buprenorphine 
in neonates. 
 
To estimate efficacy of length of treatment of a model-based optimized dose 
of buprenorphine for infants treated for NAS.  
 
To evaluate possible developmental trajectory of urinary glucuronidated 
metabolites of buprenorphine. 
 
Design 
Open label, single arm clinical trial 
 
Study Treatment 
Buprenorphine 
Sublingual 
0.075 mg ml solution 
(Buprenex, Indivior, Richmond, VA or generic equivalent) , 30% ethanol 
USP, in simple syrup USP 
Number of 
Subjects 
10 infants 
Population: 
Inclusion Criteria 
Patients eligible for participation include: 
1. ≥ 36 weeks gestation 
2. Exposure to opioids in utero 
3. Demonstration of signs and symptoms of neonatal abstinence 
syndrome requiring pharmacologic treatment 
Population: 
Exclusion 
Criteria 
Patients ineligible for participation include: 
1. Major congenital malformations and/or intrauterine growth retardation, 
defined as birth weight <2000 gm 
2. Medical illness requiring intensification of medical therapy.  This 
includes but is not limited to suspected sepsis requiring antibiotic 
therapy. 
3. Hypoglycemia requiring treatment with intravenous dextrose 
4. Bilirubin >20 mg/dL (The need for phototherapy is not exclusionary) 
5. Inability of mother to give informed consent due to co-morbid psychiatric 
diagnosis 
 
 
 
 


Modeled Dose Exposure of Sublingual Buprenorphine in the Neonatal Opioid Abstinence Syndrome 
 
Version 1.1 
 
3 
PROTOCOL VERSIONS 
 
Version 
Date 
Description 
1.0 
Feb 19, 2018 
Sent to FDA for IND  
1.1 
Apr 27, 2018 
 Added reference for Moore et. al.  buprenorphine PK/PD 
publication (PMID 29516490) 
 Adding collection of hours of duration of treatment to current 
days, if feasible (section 3.2.4.1) 
 Change phenobarbital weight used in dose calculation to birth 
weight (section 5.2.2) 
 Removal of “investigational” from pharmacy site of drug 
preparation. Drug can be made by standard hospital 
pharmacy (section 5.3.1) 
 Added “dose interval” to “dose” for reversion to control 
situation at which drug can be resumed following score > 28 
(section 6.6) 
 Various minor typographical, formatting, and stylistic changes 
 
 


Modeled Dose Exposure of Sublingual Buprenorphine in the Neonatal Opioid Abstinence Syndrome 
 
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4 
 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................. 2 
Protocol Versions............................................................................................................................. 3 
1 
Introduction ............................................................................................................................. 11 
1.1 
Background .................................................................................................................... 11 
1.2 
Proposed Study Design ................................................................................................. 12 
1.3 
Rationale for Study Design and Dose ........................................................................... 12 
1.3.1 
Single arm .................................................................................................................. 12 
1.3.2 
Buprenorphine Safety ................................................................................................ 12 
1.3.3 
Weight based vs Symptom based dosing ................................................................. 13 
1.3.4 
Justification of Buprenorphine Dose .......................................................................... 14 
1.3.4.1 
Pharmacokinetic/Pharmacodynamic (PK/PD) core model ................................ 15 
1.3.4.2 
Initial Buprenorphine Dose ................................................................................ 18 
1.3.4.3 
Simulated Uptitration ......................................................................................... 19 
1.3.4.4 
Maximum Buprenorphine Dose ......................................................................... 20 
1.3.4.5 
Simulated Wean ................................................................................................ 21 
1.3.4.6 
Cessation Buprenorphine Dose ......................................................................... 21 
1.3.4.7 
Terminal Extension of Dosing Interval ............................................................... 22 
1.3.4.8 
Final Dose Regimen Selection .......................................................................... 22 
1.3.5 
Efficacy Assessment of Length of Treatment ............................................................ 23 
1.3.6 
Safety ......................................................................................................................... 23 
1.4 
Pharmacogenetics Sample ............................................................................................ 23 
2 
Study Objectives .................................................................................................................... 24 
2.1 
Primary Objective .......................................................................................................... 24 
2.2 
Exploratory Objectives ................................................................................................... 24 
3 
Overall Design and Plan of the Study .................................................................................... 24 
3.1 
Overview ........................................................................................................................ 24 
3.2 
Endpoints ....................................................................................................................... 25 
3.2.1 
Pharmacokinetic Endpoint ......................................................................................... 25 
3.2.2 
Developmental Glucuronidation Endpoint ................................................................. 25 
3.2.3 
Safety Endpoint (exploratory) .................................................................................... 25 
3.2.3.1 
Adverse events .................................................................................................. 25 
3.2.3.2 
Serious adverse events ..................................................................................... 25 
3.2.4 
Efficacy endpoints (exploratory) ................................................................................ 25 
3.2.4.1 
Length of Treatment .......................................................................................... 25 


Modeled Dose Exposure of Sublingual Buprenorphine in the Neonatal Opioid Abstinence Syndrome 
 
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5 
3.2.4.2 
Length of Stay .................................................................................................... 26 
3.2.4.3 
Need for Supplemental Phenobarbital Use ....................................................... 26 
3.3 
Justification of Inclusion Criteria .................................................................................... 26 
3.3.1 
Preterm Infants .......................................................................................................... 26 
3.3.1.1 
Benzodiazepine Exposure ................................................................................. 26 
4 
Study Population .................................................................................................................... 27 
4.1 
Inclusion Criteria ............................................................................................................ 27 
4.2 
Exclusion Criteria ........................................................................................................... 27 
4.3 
Patient Baseline and Allocation Numbers ..................................................................... 27 
5 
Drug Administration Regimen ................................................................................................ 27 
5.1 
Identity ........................................................................................................................... 27 
5.2 
Calculation of Dose and Administration......................................................................... 28 
5.2.1 
Buprenorphine ........................................................................................................... 28 
5.2.1.1 
Starting doses .................................................................................................... 28 
5.2.1.2 
Cessation dose .................................................................................................. 28 
5.2.2 
Phenobarbital ............................................................................................................. 28 
5.3 
Drug Product Quality Control ......................................................................................... 29 
5.3.1 
Drug Preparation Procedures .................................................................................... 29 
5.3.2 
Stability ...................................................................................................................... 29 
5.3.3 
Investigational New Drug (IND) Certification ............................................................. 29 
6 
Study Procedures ................................................................................................................... 29 
6.1 
Identification of Potential Study Subjects ...................................................................... 29 
6.2 
NAS Scoring Procedures ............................................................................................... 29 
6.3 
Dose Administration....................................................................................................... 30 
6.4 
Dose Escalation ............................................................................................................. 30 
6.5 
Rescue Dose ................................................................................................................. 30 
6.6 
Weaning ......................................................................................................................... 30 
6.7 
Buprenorphine Dose Cessation and Observation ......................................................... 31 
6.8 
Maximum Dose and Use of Adjunctive Phenobarbital .................................................. 31 
6.9 
Study Data ..................................................................................................................... 32 
6.10 
Blood Samples for Pharmacokinetics ............................................................................ 32 
6.11 
Efficacy .......................................................................................................................... 33 
6.12 
Safety ............................................................................................................................. 33 
6.13 
Urine Samples for Metabolite Analysis .......................................................................... 33 
6.14 
Blood Samples for Pharmacogenomics ........................................................................ 33 
7 
Statistical/analytical methods and Power Analysis ................................................................ 34 


Modeled Dose Exposure of Sublingual Buprenorphine in the Neonatal Opioid Abstinence Syndrome 
 
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6 
7.1 
Pharmacometrics ........................................................................................................... 34 
7.2 
Power Analysis .............................................................................................................. 34 
7.3 
Efficacy, Safety and Pharmacogenetics ........................................................................ 34 
8 
Safety Parameters .................................................................................................................. 34 
8.1 
Blood volume ................................................................................................................. 35 
8.2 
Stopping Rules .............................................................................................................. 35 
8.3 
Data Safety Monitoring Plan .......................................................................................... 36 
8.4 
Certificate of Confidentiality ........................................................................................... 36 
Appendix 1: NAS Scoring system .................................................................................................. 37 
Appendix 2:  Preparation of Buprenorphine Stock Solution and stability ...................................... 38 
Appendix 3:  processing of pharmacokinetic and pharmacogenetic samples .............................. 39 
9 
References ............................................................................................................................. 40 


Modeled Dose Exposure of Sublingual Buprenorphine in the Neonatal Opioid Abstinence Syndrome 
 
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7 
Consent 
obtained 
Discharge 
NAS Score 
requiring 
treatment? 
Discharge 
Inpatient 
Observation 
2 days 
Dose Cessation 
Exclusion Criteria 
Yes 
Standard of 
Care treatment 
Monitoring of sym ptoms using MOTHER NAS Score  
Pharmacogenetic 
Sample 
Allocation 
Pharmacokinetic sampling 
 
Buprenorphine Dose  
Buprenorphine SL 
8 mcg/kg/q8 initial dose 
75 mcg/kg/day max dose 
No 
No 
Yes 
Figure 1: Study Schema 


Version 1.1 
 
8 
 
 
 
Yes 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Identify newborns exposed in utero to opioids or 
other drugs of abuse 

Maternal history or positive urine drug 
screen 
AND/OR 

Positive infant drug screen 
 
Monitor for signs of neonatal abstinence using NAS 
score.  Obtain pharmacogenetic sample 
Three NAS scores > 24 or a single score > 12 
AND  
Decision of attending to use pharmacologic therapy 
Monitor for 2-4 
days as an 
inpatient prior to 
discharge 
Buprenorphine 8 mcg/kg/q8  
 
Sum of 3 NAS scores > 24 or a single 
score > 12  
OR 
Need for rescue dose 
Continue treatment. 
 
Sum of 3 NAS scores >24 
or a single score > 12  
OR  
Need for rescue dose? 
No 
 Phenobarbital 20 mg/kg load 
with 5 mg/kg/day initiated.   
 
Phenobarbital weaned as 
tolerated by 50% reduction in 
dose followed by complete 
cessation. (Section 5.2.2) 
Yes 
Wean up to once a day when the sum of the 
previous three scores is < 18.  
 
Bottom dose is < initial buprenorphine dose 
Terminal wean to q12 then q24 dosing 
Single rescue dose at 
previous dose which 
symptoms controlled 
 
Monitor at least 1 day prior to 
discharge 
Monitor for at least 2 days in an inpatient setting prior 
to discharge. 
 
 
 Any single score > 12? 
No 
Standard of care 
monitoring and 
treatment 
Uptitration based up dose sheet placed on 
chart 
Maximum dose reached? 
 
Stability for > 2 days without dose 
Monitoring of NAS scores 
on increased dose 
Figure 2: Study Algorithm 


Modeled Dose Exposure of Sublingual Buprenorphine in the Neonatal Opioid Abstinence Syndrome 
 
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9 
Table 1: Dose Schema for Buprenorphine  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Buprenorphine 
Initial daily dose 
24 mcg/kg/day 
Initial unit dose 
8 mcg/kg q8 hours 
Maximum daily dose 
75 mcg/kg/day 
Maximum unit dose 
25 mcg/kg q8 hours 
Up-titration rate 
33% 
Maximum # of up-titrations 
4 
Weaning rate  
15% 
Cessation (bottom) dose 
< Initial dose 
Dosing interval until bottom dose (hrs) 
8 
Dose interval extension #1 at bottom dose (hrs) 
12 
Dose interval extension #2 at bottom dose (hrs) 
24 
Inpatient observation following cessation of last scheduled dose 
At least 2 days 
Inpatient observation following last rescue dose 
At least 1 day 


Version 1.1 
 
10 
 
Figure 3: Study Algorithm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial Dose 
8mcg/kg Q8 
Bottom 
dose 
Q8 
Stabilization 
Dose Q8 
Up 
Titration 
Wean until 
< initial 
dose 
3 
doses 
Bottom 
dose 
Q24 
Bottom 
dose 
Q12 
2 
doses 
1 dose 
Post dose 
Observation 
Q8 dosing 
Q12 dosing Q24 dosing 
Adjust dose 
Adjust interval 


Version 1.1 
 
11 
1 
INTRODUCTION 
 
1.1 Background 
 
Neonatal abstinence syndrome (NAS) is a set of signs of withdrawal in an infant with in utero exposure to 
opioids.1 Cardinal manifestations include increased muscle tone, autonomic instability, irritability, poor 
sucking reflex, gastrointestinal symptoms, and impaired weight gain. All infants are treated with non-
pharmacologic methods such as swaddling, rooming in with mother, and minimization of stimuli.2  Despite 
these measures, ~ 50% of infants require pharmacologic treatment to ensure proper growth and 
development. While the optimal pharmacologic treatment for NAS has not been identified, expert review 
identifies an opioid as the primary therapy.3 In the US 80% of infants are treated with morphine and 20% 
with methadone.4  Sublingual buprenorphine has been demonstrated to be safe and effective in an open 
label clinical trial conducted by Thomas Jefferson University investigators [NCT00521248].5,6 The BBORN 
(Blinded Buprenorphine OR Neonatal morphine solution) double blinded clinical trial [NCT01452789] 
comparing buprenorphine to morphine for NAS confirmed the efficacy in a double blind fashion.7 The 
external validity of this finding was supported by retrospective examination of buprenorphine used in a 
treatment paradigm, with a reduction in length of treatment of ~30%.8,9 
  
Dose selection for both the phase 1 trial and the efficacy trial (BBORN) were empirically derived.  A 
population pharmacokinetic model for buprenorphine in NAS has been published.10 In addition a pre-
specified endpoint for the BBORN trial was a pharmacokinetic analysis of buprenorphine. A 
pharmacokinetic/pharmacodynamic model from the BBORN study has been created.11 The time to control 
of symptoms was directly tied to buprenorphine exposure, which itself appeared to be driven primarily by 
clearance. Among the strengths of pharmacometric models is the ability to simulate in silico many potential 
dose regimens. In this manner, a dose regimen can be chosen that achieves exposures associated with 
efficacy. This approach also allows for incorporation of covariates of drug exposure or response to 
treatment. This is much safer and efficient than the traditional approach of choosing an empiric dose that 
would need to be tested in clinical trial.12 An ideal dose would quickly reach this exposure while maintaining 
a good safety margin. There was no evidence of decline in respiratory rate in infants treated with higher 
doses of buprenorphine compared to lower doses, or those treated with buprenorphine compared to those 
treated with morphine. This may allow a higher initial dose to more quickly reach therapeutic buprenorphine 
concentrations. This ultimately could lead to shorter lengths of treatment and stay, though this goal is 
outside of the scope of the current proposed project. 
 
In summary, buprenorphine at the dose and schedule used in clinical trials has been demonstrated to be 
safe and effective. The goal of the proposed study is to simulate a dose of sublingual buprenorphine for 


Modeled Dose Exposure of Sublingual Buprenorphine in the Neonatal Opioid Abstinence Syndrome 
 
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12 
NAS using pharmacometric modeling techniques. This dose will be tested in infants requiring treatment for 
NAS. Pharmacokinetic samples would be collected and used to confirm and refine the pharmacokinetic 
model. The proposed study would allow broad examination and refinement of the exposure/response 
relationship. This optimized dose could later be used in an efficacy trial, and can serve other modeling 
purposes such as an eventual changes to the weaning dose to twice or even once a day for outpatient 
treatment. 
 
1.2 Proposed Study Design 
This is an open label, single arm, single site, dose finding clinical trial. 
 
1.3 Rationale for Study Design and Dose 
 
1.3.1 Single arm 
Buprenorphine became the current standard of care for NAS pharmacologic treatment at Thomas Jefferson 
University Hospital.  The goal of this study is to examine buprenorphine pharmacokinetics following an 
altered dose regimen. The study will not explore comparative safety or efficacy of buprenorphine or 
morphine. Therefore, a buprenorphine or morphine standard of care group would provide limited additional 
information.  
 
1.3.2 Buprenorphine Safety 
Pharmacologic treatment of NAS in a highly monitored inpatient setting is safe.13 This has proved true for 
buprenorphine. A listing of all adverse events occurring in three clinical trials of buprenorphine at Thomas 
Jefferson University Hospital is listed in Table 2. This represents total adverse events, and some infants 
had more than one adverse event. All were “definitely not” or “probably not” related to study drug. There 
were four serious adverse events, none of which was drug related. This safety profile has been mirrored in 
published studies of 212 infants treated in Cincinnati, Ohio.8,9  
 
Modeling from BBORN data demonstrated no respiratory relationship between either buprenorphine or 
norbuprenorphine exposure. Buprenorphine in adults has a modestly correlated dose response 
relationship, with a much better exposure response as defined by amelioration of symptoms14 and CNS mu 
opioid binding.15,16  There have been no observed episodes of excessive sedation, respiratory depression, 
or aspiration after >3,500 doses of sublingual buprenorphine administered to >60 infants in the phase 1 
and BBORN trials. No respiratory depression was described by Hall in the clinical use of buprenorphine for 
NAS in Cincinnati (personal communication, S Wexelblatt), nor in the current therapeutic use at Thomas 


Modeled Dose Exposure of Sublingual Buprenorphine in the Neonatal Opioid Abstinence Syndrome 
 
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13 
Jefferson University Hospital. These findings mirror years of clinical experience with morphine administered 
in a monitored setting, as well as wide experience with methadone at other sites. Hepatic safety is similarly 
reassuring based on an adolescent cohort study.17 There was no hepatic toxicity noted in a 2008 case 
series of 84 pediatric overdoses of buprenorphine.18 In clinical trial experience at Thomas Jefferson 
University Hospital, there was an episode of elevated transaminase level in an infant with unrelated 
cytomegalovirus. There were no other elevations of liver enzymes in any other subjects. These lines of 
evidence strongly support the wide therapeutic index of the partial agonist buprenorphine at exposures 
anticipated using a new dosing regimen. 
 
Table 2: Adverse Events Observed in Buprenorphine Clinical Trials at Thomas Jefferson University 
 
 
Buprenorphine 
(n=64) 
Morphine 
(n=60) 
Anemia 
1 
0 
Skin conditions 
7 
3 
Gastrointestinal conditions 
4 
6 
Respiratory conditions 
1 
2 
Tachycardia 
1 
0 
Umbilical granuloma 
1 
0 
Urinary conditions 
1 
1 
Ocular conditions 
0 
1 
Clavicle birth fracture 
1 
0 
Hepatic conditions 
1 
0 
Inguinal hernia repair* 
0 
1 
Supraglottoplasty* 
1 
0 
Cytomegalovirus infection* 
1 
0 
Seizure* 
1 
0 
Total number of adverse events 
21 (33%) 
14 (23%) 
*unrelated serious adverse events 
 
1.3.3 Weight based vs Symptom based dosing 
 
This trial will use a weight-based approach, which is regimen in all published buprenorphine clinical trials 
in NAS. This method employs a single weight-based dose for all infants regardless of the initial NAS score. 
A small number other centers using morphine employ a symptom-based approach. This symptom-based 
regimen uses a weight-independent dose that varies with the severity of disease. (Figure 3) The weight-
based approach accounts for variability due to infant mass, at the expense of being less tailored to individual 
disease severity. The weight-based approach is most commonly used with almost all other medications 
used in the neonatology unit. Symptom based dosing captures variability in disease severity but will result 
in more varied initial dose. While the weight based method is much more commonly used, there is no 
consensus as to which is the preferred method, nor are there any comparative trials.19,20 


Modeled Dose Exposure of Sublingual Buprenorphine in the Neonatal Opioid Abstinence Syndrome 
 
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14 
 
Figure 4: Representative Weight and Symptom Based Approaches to Morphine Dosing 
 
 
A concern about a weight-independent dose calculation is variability in buprenorphine exposure based 
upon infant size. For smaller infants with severe symptoms, there is a theoretical concern of an excess 
dose leading to respiratory depression. However, this concern is less likely due to partial agonism of 
buprenorphine and a ceiling effect on respiratory depression in adults.21 Despite this safety profile that is 
likely to be favorable, the weight based approach has a number of compelling advantages. Foremost is that 
the original modeling exercise is based upon the BBORN trial, in which doses and titration schedules were 
weight based. Adding the additional variable of a new titration regimen will complicate simulation of doses. 
Secondly, the culture and practice of clinicians at Thomas Jefferson University Hospital is to use a weight-
based approach. Maintaining this approach for both study and non-study infants will help to standardize 
care within the context of the clinical trial. There is greater clinician acceptance of the weight-based 
approach external to Thomas Jefferson University. Lastly, the use of a weight-based approach in this 
pharmacokinetic-driven protocol will not substantially impact the ability to test the symptom based approach 
in subsequent phase 2 and 3 studies. The primary goal of the current investigation is primarily investigating 
exposures with alternated dose regimens, with a secondary goal of attempting to define exposure response. 
 
1.3.4 Justification of Buprenorphine Dose 
This protocol seeks to explore additional dose regimens which will be used to refine a pharmacometric 


Modeled Dose Exposure of Sublingual Buprenorphine in the Neonatal Opioid Abstinence Syndrome 
 
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15 
model of buprenorphine in NAS. This model refinement will aid in increasing precision with which future 
simulations can be performed. The goal of these simulations will be to inform subsequent clinical trials to 
optimize drug dosing. The parameters to be examined are 1) initial dose, 2) uptitration rate, 3) maximum 
dose, 4) weaning rate, 5) cessation dose, and 6) dosing interval. The study regimen employs a terminal 
wean in which the final adjustments are an elongation of the dosing interval rather than a reduction in the 
dose. To reduce confusion to parents and clinicians, what has been termed until now the “cessation dose” 
will be generally referred to as the “bottom dose”.  
 
Table 3: Final Dosing Plan. Proposed dose schema to be used in this trial (BPHORE) is compared to that 
used in the BBORN trial 
 
Trial 
BPHORE 
BBORN 
Initial dose (mcg/kg) 
8 
5.3 
Uptitration rate 
33% 
25% 
Maximum number of up-titrations  
4 
6 
Maximum dose (mcg/kg) 
25 
20 
Weaning rate 
15% 
10% 
Cessation (“bottom”) dose 
< 100% of initial dose 
< 110% of initial dose 
Dosing interval until bottom dose (hrs) 
8 
8 
Dose interval extension #1 at bottom dose (hrs) 
12 
N/A 
Dose interval extension #2 at bottom dose (hrs) 
24 
N/A 
 
1.3.4.1 Pharmacokinetic/Pharmacodynamic (PK/PD) core model 
The BBORN trial used an initial dose of 5.3 mcg/kg/q8, with a maximum dose of 20 mcg/kg/q8. This 
approach was associated with a mean length of treatment of 15 days, compared to 28 days with the 
standard of care morphine regimen. Based upon the pharmacometric model developed by Ng from the 
phase 1 data at Thomas Jefferson University Hospital,10 Moore and Ng developed a revised model from 
the BBORN trial.11 This model was based upon 265 samples of buprenorphine and norbuprenorphine, and 
4,373 NAS scores collected from 28 infants. The model was shown to reasonably predict the BBORN data 
with a mean squared error of 0.062 and root mean squared error of 0.251. An adapted PK model was fit to 
the data and extended to describe the metabolite concentration-time profile. An exposure-response 
relationship was found between buprenorphine and NAS symptom progression, but not for respiratory rate. 
Time to NAS stabilization was found to decrease with increasing buprenorphine AUC. Neonates with a 
lower clearance had a shorter time to stabilization as shown in Figure 4a. Time to stabilization of NAS 
scores was best correlated with buprenorphine exposure. Neonates with similar severity of NAS generally 
stabilized around the same time. Furthermore, for any given group of NAS severity, neonates exposed to 
higher concentrations of buprenorphine tended to stabilize faster. While buprenorphine and 


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norbuprenorphine concentrations were highly correlated, buprenorphine was found to be a more significant 
driver of PD effects. Though the primary metabolite norbuprenorphine has a greater respiratory effect than 
the parent in animal models,22 it is a substrate of p-glycoprotein and with very little CNS penetration.23,24 
For this reason dosing simulations will be based primarily on buprenorphine rather than metabolite.  
 
Figure 5: Relationship of Buprenorphine Concentration to Control of NAS Symptoms 
A) Effect of Changing Clearance on Time 
to NAS Stabilization (TNS). The size of 
each dot represents each neonate’s 
maximum Finnegan Score (FNS).  
 
 
 
 
 
 
 
 
B) Relationship between TNS and AUC. 
Each neonate included is represented by 
a point, which represents the TNS and 
AUC of buprenorphine until that time. 
The graph is divided into quartiles of AUC 
by the 4 black lines and is divided into 
quartiles of average concentration by the 
colors. 
The 
max 
FNS 
score 
is 
represented by the size of each dot.  
 


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C) Relationship between TNS and 
average concentration. Each neonate 
included is represented by a point, 
which represents the TNS and average 
concentration of buprenorphine until 
that time. The graph is divided into 
quartiles of average concentration by 
the colors and the black lines. The max 
FNS score is represented by the size of 
each dot.  
 
 
 
D) NAS Survival Analysis. This graph 
represents the predicted stabilization of 
NAS over time for a theoretical neonate 
at 
one 
of 
the 
4 
quartiles 
of 
buprenorphine concentration and a 
max FNS of 11. 
 
 
 
Based upon the exposure response relationship, several summary observations can be made from the 
PK/PD modeling of buprenorphine in NAS. 
 
Efficacy of time to stabilization is driven primarily by buprenorphine exposure, implying that most 
of the variability in dose response has a pharmacokinetic basis. 
 
Exposure is driven primarily by changes in clearance, with no clearly identified covariates that can 
predict pharmacokinetic variability. 
 
There was no identifiable change in respiratory rate associated with buprenorphine exposure. 
 
In light of limited sampling close to dose administration, absorption kinetics are not well defined. 
 
A pharmacometric simulation created using the model was employed with a goal of exploring variations in 
dosage regimens. The final PK/PD model was utilized to explore exposure differences by performing dose 
ranging simulations, from 0.1 to 15 mcg/kg doses. An adaptive simulation design was developed to account 
for the dynamic changes in withdrawal due to buprenorphine exposure based on each of the simulated 
doses. Stochastic simulations used fixed parameter values for PK parameters and inter-individual 


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variability. However, residual variability was incorporated to account for random effects. This was modeled 
by assuming a normal distribution and randomly sampling from the distribution from the final PK/PD model 
with 100 simulations per subject, resulting in a probability distribution for the expected exposure for each 
simulated dose. 
 
1.3.4.2 Initial Buprenorphine Dose 
A simulation using initial doses of 0.1, 0.5, 1, 5.3, 8, 10 and 15 mcg/kg was run for each individual patient 
and compared to actual observed time to stabilization. (Figure 6)  
 
Figure 6: Modeled Time to Stabilization Using BBORN Uptitration (25%) and Weaning (10%) Rates. 
Grey boxes identify individual subjects in the BBORN trial. Simulated doses are listed, with mean time (light 
pink dot), interquartile ranges and actual observed (OBS) values in dark pink circle. 
 
 
Time to stabilization was defined as the time after initiation of treatment at which there were no up-titrations 
in dose for 48 hours and the patient had first weaning dose. Specific parameters used to define this in the 


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simulation were based upon the weaning algorithm (Figure 2), which was the time point at which there was 
a single Finnegan score <6, cumulative score over previous 3 was < 17, weaning dose was employed, and 
no up titration. These simulations suggested there was limited efficacy advantage beyond an initial dose of 
8 mcg/kg. This dose represents an only modest increase over that used in clinical trials and a treatment 
setting, and as such would likely to be accepted by clinicians involved in the proposed trial.  
 
1.3.4.3 Simulated Uptitration  
The BBORN trial used an uptitration rate of 25%. A 33% and 50% up-titration rate were simulated (Table 
4, reference in shaded box) at the 8 mcg/kg q8 initial dose. The endpoint was time to stabilization, defined 
as 48 hours without need for up-titration of dose.  
 
Table 4: Simulated Time to Stabilization (hours) with Varied Uptitration Rate 
 
 
Time to stabilization (hours) 
Δ time to stabilization from reference 
25% uptitration rate (hours) 
Initial dose 
(mcg/kg) 
Titration rate 
Titration rate 
25% 
33% 
50% 
33%  
50%  
5.3 
153.8 
139.2 
126.0 
-14.6 
-27.8 
8.0 
137.3 
131.5 
118.0 
-5.8 
-19.3 
Shaded box represents the dose regimen used in the BBORN trial. 
 
Both 33% and 50% provide advantages over the 25% uptitration rate in meeting the time to stabilization. 
However, as a higher initial dose is being used, the use of a 50% uptitration rate would entail large, rapid 
increase in exposures. In the BBORN trial there were 6 titrations before maximum dose was reached. Even 
with increasing the maximum dose, the number of titrations before need for a secondary agent drops. At a 
50% increase, maximum dose is reached after only three uptitrations. (Table 5) 
Table 5. Uptitration Steps to Maximum Dose 
 
Uptitration step 
Uptitration 
rate 
Initial 
dose 
(mcg/kg) 
1 
2 
3 
4 
5 
6 
Max daily 
dose 
(mcg/kg) 
25% 
5.3 
6.6 
8.3 
10.4 
12.9 
16.2 
20.0 
60.0 
25% 
8 
10.0 
12.5 
15.6 
19.5 
25.0 
 
75.0 
33% 
8 
10.6 
14.2 
18.8 
25.0 
 
 
75.0 
50% 
8 
12.0 
18.0 
25.0 
 
 
 
75.0 
Shaded row represents the dose regimen used in the BBORN trial. 


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Based on the favorable simulated efficacy advantages, combined with a conservative approach to rate of 
increase and ability to titrate before reaching maximum dose and need for adjunctive phenobarbital, a 
uptitration rate of 33% will be used. 
 
1.3.4.4 Maximum Buprenorphine Dose 
The maximum dose employed in all reported studies has been 20 mcg/kg q8. The primary safety concern 
with an opioid treatment is respiratory depression. No respiratory depression was noted clinically in either 
buprenorphine or morphine arms in either the phase 1 or BBORN studies, though in BBORN the morphine 
patients in had on average a 4.4 breath per minute slower respiratory rate. In the PK/PD model, there was 
no relationship between buprenorphine exposure and respiratory rate. Respiratory depression using 
morphine and methadone for NAS in an inpatient setting is unheard of. Maximum doses of morphine vary 
across units. The Thomas Jefferson University Hospital maximum is 1.25 mg/kg, though doses as high as 
1.5 mg/kg have been used on occasion in difficult to control cases. These values are similar to that 
described by O’Grady in a survey of units in the United Kingdom.25 Of interest, one third of surveyed units 
had no stated maximum dose used but instead described a dose driven by symptoms. The safety margin 
of buprenorphine is expected to be much wider than morphine or methadone. It is a partial rather than full 
mu opioid receptor agonist and has superior respiratory safety profile in adults and adolescents. As such, 
an increase in the maximum dose to 25 mcg/kg q8 will be tested. Use of the higher dose will allow a fuller 
exploration of the pharmacokinetics and exposure of buprenorphine, and will strengthen the ability to 
simulate dose regimens to be subsequently tested in a phase 2 study.  
 
Exposures of buprenorphine will be well below those anticipated to incur any safety issues. The 
buprenorphine exposure response relationship varies with specific pharmacodynamic endpoint measured, 
but for respiratory rate depression the plateau occurs at 16 mg of sublingual solution in adult, opioid naïve 
subjects. This dose is associated with a Cmax of ~10 ng/ml.21 At that exposure a decrease in respiratory 
rate was observed, but none of the opioid naïve volunteers had clinically significant respiratory depression. 
Recent investigations confirm that the ceiling effect is pharmacodynamic and not pharmacokinetic, as there 
is linear dose to exposure relationship, with serum concentration of >170 ng/ml well tolerated in opioid 
experienced volunteers.26 In infants with opioid exposure in utero, extrapolation from opioid experienced 
compared to naïve adult volunteers is more applicable. The highest recorded serum concentration in either 
BBORN or the phase 1 trial was 18 ng/ml without any observed respiratory depression or excess 
somnolence. The mean concentration in BBORN of those above the limit of quantification was 0.5 ng/ml. 
 
 


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1.3.4.5 Simulated Wean  
A 15% and 25% weaning rate was simulated compared to the current standard of 15% (Table 7, reference 
in shaded box) at the 8 mcg/kg q8 dose. The endpoint was time to wean, defined as the time in hours from 
start of treatment to last dose (including any rescued doses). 
 
Table 7: Simulated Time to Wean (hours) with Varied Wean Rate 
 
 
Time to wean (hours) 
Δ time from reference 10% 
weaning rate (hours) 
Initial Dose 
(mcg/kg) 
Weaning rate 
Weaning rate 
10%  
15%  
25%  
15%  
25%  
5.3 
166.1 
125.1 
102.4 
-41.1 
-63.7 
8 
155.7 
112.8 
97.5 
-42.9 
-58.2 
Shaded box represents the dose regimen used in the BBORN trial. 
 
1.3.4.6 Cessation Buprenorphine Dose 
In the BBORN trial, the cessation dose was within 10% of the initial dose. The mean dose at time of 
cessation was 5.3 mcg/kg, based upon actual weight at the time of cessation. No infants required 
readmission following discharge, however 44% required a rescue dose after scheduled dosing was 
completed. The current trial will define the cessation dose as the dose that is equal or less than the initial 
dose in mcg (and not a weight normalized dose of mcg/kg).  Most infants will regain their birthweight at 
about the time for cessation. A simulation was performed to estimate the impact of the proposed cessation 
dose (Table 8).  This simulation was based upon cessation of all dosing at the cessation dose without any 
extension of interval. Despite a higher cessation dose, the model predicted less of a need for rescue doses. 
Symptom driven administration of rescue doses ensure that there will not be inadequate treatment of 
symptoms, even if the precision of the modeled response is less than expected. 
 
 
 
 


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Rescue 
doses if 
needed 
Table 8: Simulated Time to Wean (hours) with Varied Wean Rate 
 
 
BPHORE 
BBORN 
Initial dose (mcg/kg) 
8 
5.3 
Cessation dose 
< 100% of the initial dose 
< 110% of the initial dose 
Initial mean infant weight used in 
simulation (gm) 
2988 
2988 
Simulated weight at cessation (gm) 
2940 
3010 
Simulated dose at cessation (mcg) 
27.1 
18.1 
Simulated normalized dose at 
cessation (mcg/kg) 
9.3 
6.1 
Simulated % of infants who would 
require post cessation rescue dose 
25% 
39% 
Actual % of infants in BBORN 
requiring post cessation rescue dose 
N/A 
44% 
Actual median birthweight in BBORN 
(gm) 
N/A 
3040 
 
1.3.4.7 Terminal Extension of Dosing Interval 
In BBORN 44% of infants required a post cessation rescue dose of buprenorphine. The last administered 
dose was used for determination of the primary endpoint of length of treatment in the BBORN trial. Though 
the model suggests a lower rate of post dose cessation, the cessation dose is higher than in BBORN and 
remains relatively high. Rescue dose after a patient has cessation of medication is often seen as weaning 
“failure” by parents and some clinicians, rather than part of the weaning process. As the goal of this protocol 
is to explore alternate dosing regimens, the protocol will at the cessation or “bottom” dose switch over to a 
weaning of dose interval. This is represented in Figure 3 and below. The impact of this change in interval 
has not been formally simulated, but it is anticipated that this will reduce the number of post cessation 
rescue doses. The sample size of this trial will make formal assessment of this approach on clinical 
endpoints of length of treatment not possible, but the exercise will assist with exploration of regimen 
optimization. 
 
 
 
1.3.4.8 Final Dose Regimen Selection 
Simulated regimens suggest additional efficacy when uptitration rate is extended from 30 to 50%, as well 
as decreased treatment duration when weaning rate is increased from 15 to 25%. In both cases, the larger 


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jumps reduce the discriminatory power of the regimen to avoid higher buprenorphine doses in infants who 
would have either been managed with lower dose of buprenorphine afforded by a slower uptitration, or 
those who would have benefited from a slower down titration rate. In addition, the incorporation of a new 
maximum dose is challenging to accurately capture using modeling techniques. As the goal of this protocol 
is to gather information to refine an existing model, it is prudent to undertake more modest dose and 
regimen changes. 
 
1.3.5 Efficacy Assessment of Length of Treatment 
Buprenorphine efficacy has been demonstrated in infants even with concentrations below the 0.7 ng/ml 
considered to be the level at which relief of adult abstinence symptoms begins.14 The model of Moore and 
Ng suggest the value in infants to be 0.8 ng/ml. Using the pharmacometric model used to describe the 
BBORN data, a simulation was created to predict the range of expected exposures associated with the 
proposed regimen. Compared to 5.3 mcg/kg, an initial dose of 8 mcg/kg would did not substantially change 
the mean number of titrations needed to reach stabilization, but did reduce the time to stabilization. The 
small sample size and lack of comparator group make an assessment of the endpoints of length of 
treatment, length of stay, or need for phenobarbital rescue within this study to be at best exploratory.  
 
1.3.6 Safety  
There has been no indication of idiosyncratic or dose-related toxicity. Respiratory related toxicity is of the 
largest concern with dosing of an opioid. In the BBORN trial there were no episodes of clinical respiratory 
depression. Model based analysis implied that at any time during the treatment period, the mean respiratory 
rate in morphine treated infants was lower by 4.4 breaths per minute (95% CI: 0.7, 8.1; p=0.020) as 
compared to buprenorphine treated infants in the same strata. Furthermore, in the pharmacometric 
modeling analysis there was no relationship between observed concentration of buprenorphine and 
respiratory rate. Hysteresis plots and patient-level data were also analyzed but showed no relationship 
between buprenorphine or norbuprenorphine concentration and respiratory rate. Considering the wide 
therapeutic index of buprenorphine in multiple populations, the modest increase in maximum dose is 
considered to have low risk for dose-dependent adverse effects.  
 
1.4 Pharmacogenetics Sample 
Pharmacogenetic variants can lead to differences to drug exposure. Since the primary endpoint of the trial 
is pharmacokinetic, a blood sample for pharmacogenetics will be obtained from infants enrolled. 
Pharmacogenetic variation in the neonatal abstinence syndrome has been primarily based upon differences 
in receptor polymorphisms such as OPMR1 or genes associated with neurotransmitter disposition such as 


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prepronociceptin (PNOC), catechol-O-methyltransferase (COMT) genes.27-30 There has not been 
demonstration of pharmacogenetic-linked drug metabolism or transport on outcomes in NAS. For this 
reason there will not be an a priori list of genes to be surveyed. In addition, the small number of patients to 
be enrolled will allow very limited power to differentiate drug exposure according to genotype. However, as 
the genetic analysis of the BBORN trial is currently underway, it is possible that there will be an emergent 
determinant of drug disposition based upon genotype. 
 
2 
STUDY OBJECTIVES 
 
2.1 Primary Objective 
To define buprenorphine pharmacokinetic exposure in infants treated with buprenorphine for 
neonatal abstinence syndrome (NAS) using a model-based optimized dose. 
 
2.2 Exploratory Objectives 
1) To examine the safety of a model-based optimized dose of buprenorphine in neonates. 
 
2)  To estimate efficacy of length of treatment of a model-based optimized dose of buprenorphine for 
infants treated for NAS. 
 
3) To evaluate possible developmental trajectory of urinary glucuronidated metabolites of 
buprenorphine. 
 
3 
OVERALL DESIGN AND PLAN OF THE STUDY 
 
3.1 Overview 
This is a single-site, open label clinical trial. Potential patients will be identified in the prenatal period by 
staff of the Thomas Jefferson University Family Center and by daily screening of the inpatient census at 
Thomas Jefferson University Hospital. Infants at risk for NAS will have abstinence assessed using the 
MOTHER scoring instrument,31 which is based upon Finnegan Score and will hereafter be called the “NAS 
score” (Appendix 1).  This is the standard instrument used at Thomas Jefferson University Hospital. A need 
for initiation of treatment will be defined as any consecutive 3 scores adding up to ≥24 or any single score 
≥12, and the clinical decision of the attending physician that the infant requires pharmacologic therapy 
(Figure 2).  When the threshold for initiation of treatment is reached, a re-review of inclusion and exclusion 
criteria will take place prior to dose administration. NAS scores will be obtained every 4 hours. Dose 
assessment will take place daily. If the three previous NAS scores are ≥24, a dose advancement will take 
place (at the discretion of the neonatologist). Buprenorphine dose will be increased by 33% per uptitration. 
After two days of stability, patients will have weaning of dose until initial dose is reached. 


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3.2 Endpoints 
3.2.1 Pharmacokinetic Endpoint 
Sparse sampling will be used to generate an estimate of pharmacokinetic parameters and intersubject 
variability of sublingual buprenorphine. Population PK generated exposure profile of the revised dose 
schema will be compared to model simulations.  
 
3.2.2 Developmental Glucuronidation Endpoint 
Diaper cotton will be used to collect urine every 5-7 days. Glucuronidated buprenorphine metabolites will 
be assayed. The relative fraction of each glucuronidated metabolite will be reviewed as a function of post-
natal age. Developmental phase 2 metabolic processes will be estimated on an exploratory basis using 
glucuronidated metabolites collected from spot urine. 
 
3.2.3 Safety Endpoint (exploratory) 
3.2.3.1 Adverse events 
Adverse events will be recorded in the patient’s research chart using a standardized form. Events will be 
graded by blinded investigators. Adverse events will be graded by an investigator according to a severity 
score (mild, moderate, severe). 
 
3.2.3.2 Serious adverse events 
A serious adverse event is one that results in death, permanent disability, prolongation of hospitalization, 
or judged by an investigator to be a significant medical event.  All serious adverse events will be reported 
to the Institutional Review Board, and the FDA. An independent safety monitor will review all serious 
adverse events. 
 
 
3.2.4 Efficacy endpoints (exploratory) 
3.2.4.1 Length of Treatment  
Length of treatment is defined as the number of calendar days when treatment was initiated until the last 
dose of study drug using 12 midnight as the cut off between days. If feasible, hours of treatment from first 
until last dose of buprenorphine will be recorded. 
 


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3.2.4.2 Length of Stay  
Length of stay is defined as the number of calendar days from date of birth to date of discharge from the 
hospital.   
 
3.2.4.3 Need for Supplemental Phenobarbital Use 
Phenobarbital is used as a rescue therapy when maximum opioid replacement therapy dose is reached 
without adequate resolution of symptoms. The number of infants requiring phenobarbital rescue will be 
recorded.   
 
3.3 Justification of Inclusion Criteria 
 
3.3.1 Preterm Infants 
Preterm infants have a well-described natural history of NAS and a need for treatment that differs from term 
infants.32,33 The Finnegan score does differ in preterm infants,34 but it remains the standard instrument for 
gauging withdrawal severity. The preterm population thus appears to differ from term infants in 
manifestations of disease. However, treatment approaches are similar and ~30% of infants at risk for NAS 
are premature. Barrett described the intravenous use of buprenorphine in 12 infants between the ages of 
27-31 weeks with no safety issues identified.35 Hall reported infants 34 weeks and older in his descriptions 
of infants treated with buprenorphine in NAS.8,9 The buprenorphine treated infants in BBORN had a mean 
gestational age of 37.9 (SD 1.9). While inclusion of premature infants appears safe, this is a dose finding 
study with expected differential clearance based upon developmental stage. For this reason, the inclusion 
criteria will be widened slightly to >36 weeks. This will serve to expand the generalizability of data. Given 
the small sample size and few infants enrolled between 36-37 weeks, there likely will be only modest ability 
to detect maturation associated differences in drug exposure. 
 
3.3.1.1 Benzodiazepine Exposure 
A retrospective study at Thomas Jefferson University Hospital demonstrated that the length of NAS 
treatment for benzodiazepine exposed infants between 2000-2006 was prolonged,32 a finding confirmed in 
other reports.36 Hall reported 40% of buprenorphine treated infants as having been polysubstance exposed, 
though the exact break out of benzodiazepine exposures were not included. The unpublished MOP Plus 
trial at Thomas Jefferson University Hospital enrolled specifically infants with benzodiazepine exposure. 
[NCT01671410] No safety issues were identified in any of the six infants enrolled. There is not an 
anticipated pharmacokinetic interaction from in utero exposure. Inclusion of infants with benzodiazepine 


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exposure is thus safe and will increase the generalizability of findings. 
 
4 
STUDY POPULATION 
 
4.1 Inclusion Criteria 
Patients eligible for participation include: 
1. ≥ 36 weeks gestation 
2. Exposure to opioids in utero  
3. Demonstration of signs and symptoms of neonatal abstinence syndrome requiring treatment 
4.2 Exclusion Criteria 
Patients ineligible for participation include: 
1. Major congenital malformations and/or intrauterine growth retardation, defined as birth weight 
<2000 gm  
2. Medical illness requiring intensification of medical therapy.  This includes but is not limited to 
suspected sepsis requiring antibiotic therapy. 
3. Hypoglycemia requiring treatment with intravenous dextrose 
4. Bilirubin >20 mg/dL (The need for phototherapy is not exclusionary) 
5. Inability of mother to give informed consent due to co-morbid psychiatric diagnosis 
 
4.3 Patient Baseline and Allocation Numbers 
All patients for whom consent is obtained will be given a four-digit baseline screening number that begins 
with sequence 4001. Patients who require treatment and are allocated to will receive a three-digit allocation 
number that begins with sequence 501. 
 
5 
DRUG ADMINISTRATION REGIMEN 
 
5.1 Identity 
All study drug will be prepared in bulk solution, distributed to the patient ward, and unit dosed by nursing in 
1 mL pediatric dispensing vials (Healthcare Logistics Cat. # 7870 or equivalent). Preparation and stability 
is listed in Appendix 2.   
 


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5.2 Calculation of Dose and Administration 
 
5.2.1 Buprenorphine 
Buprenorphine solution will consist of simple syrup, ethanol 30% final volume, and buprenorphine.  The 
final concentration of buprenorphine is 0.075 mg/mL total volume. The patient weight at the initiation of 
dosing will be used for the calculation of all subsequent doses of buprenorphine. The calculation of 
maximum dose will be based upon weight at time of administration. Dose will be communicated with the 
primary team by way of a dose sheet. The primary team will order the buprenorphine using the electronic 
medical record. This includes protocol specified maximum of 75 mcg/kg/day for buprenorphine. To allow 
for alterations in sleeping and feeding schedules, each dose of buprenorphine can be administered +/- 30 
minutes around the nominal time point for that dose. Actual time that each dose was administered must be 
recorded in the medical record. The study drug administrator will hold the child’s head at approximately 45 
degrees, gently move the tongue to the side, administer the drug under the tongue, and immediately place 
a pacifier in the mouth to reduce swallowing of drug. If the volume of the drug is >0.5 ml, half of the drug 
will be administered, followed by the remainder of the dose in approximately 2 minutes. 
. 
5.2.1.1 Starting doses 
The starting daily dose for buprenorphine will be 24 mcg/kg/day (8 mcg/kg/q8 hours). 
 
5.2.1.2 Cessation dose 
The cessation dose will be < initiation dose.  
 
5.2.2 Phenobarbital 
The hospital standard of care phenobarbital elixir formulation (20 mg/5 ml or similar equivalent) will be used. 
Birth weight will be used for the calculation of phenobarbital loading and maintenance dose. A loading dose 
20 mg/kg followed by daily oral dose of 5 mg/kg/day will be used. When buprenorphine is weaned to 50% 
of highest dose, phenobarbital is decreased to 2.5 mg/kg/day. After three additional opioid weans, 
phenobarbital will be discontinued and the buprenorphine weaned until cessation dose was met. 
 
 


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5.3 Drug Product Quality Control 
 
5.3.1 Drug Preparation Procedures 
Preparation of stock solution for study drug will take place in the pharmacy of Thomas Jefferson University 
Hospital. 
 
5.3.2 Stability 
Buprenorphine solution will be used within 30 days of stock drug preparation. Buprenorphine has stability 
in plastic syringes for at least 7 days at room temperature.37  
 
5.3.3 Investigational New Drug (IND) Certification 
This protocol is being conducted under existing IND # 68,403 
 
6 
STUDY PROCEDURES  
 
6.1 Identification of Potential Study Subjects 
Potential subjects will be identified through the outpatient treatment clinics and by review of all infants at 
risk for NAS based on maternally identified use of opioid therapy. All infants at risk for NAS have standard 
care NAS scoring conducted every 4 hours. Consented infants with the sum of three scores >24 or more 
or a single score of >12 will be eligible for allocation. The ultimate decision to initiate treatment will be that 
of the treating pediatrician. A child will be allocated only after a definite decision to treat is made. All infants 
who have genetic consent obtained will have a blood sample for DNA analysis obtained, ideally at the time 
of a clinically indicated draw.  
 
Infants not meeting the treatment threshold criteria will be observed at least 3 days postpartum in an 
inpatient setting prior to discharge. Infants who have the sum of three scores >18 but <24 can be observed 
additional days as inpatients at the discretion of the attending physician. 
 
6.2 NAS Scoring Procedures 
NAS scoring for each subject will take place at 4 hour intervals (+/- 30 minutes to account for sleeping and 
feeding schedule). The exact time of scoring will be recorded in the medical record.   
 


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6.3 Dose Administration 
From initiation through reaching bottom dose, buprenorphine is administered every eight hours. After 
reaching bottom dose (< initial dose), the next weaning step is q12 dosing for at least two doses, and then 
following next weaning step q24 hour dosing interval.  There is a +/- 30 minute interval around each nominal 
time point to account for sleeping and feeding schedule. A dose should not be delayed more than 30 
minutes past nominal dosing time due to sleep. If dosing occurs at a time different from the specified 
nominal time, the next dose will be scheduled to take place 4 hours following the actual dose administration. 
The exact time of drug administration will be recorded in the medical record.   
 
6.4 Dose Escalation 
Dose escalation of 33% of the previous dose will take place if  
 
the sum of 3 NAS scores is >24 or a single score is >12 
OR 
 
a rescue dose was administered [section 6.5]. 
 
To mimic actual clinical care, dose advancement will generally take place in daylight hours when the primary 
team caring for the patient is present. However, dose advancement may take place when the primary team 
is not present (such as would occur on evenings and nights). All dose decisions will be made based on the 
three most recent scores. No more than one dose escalation can take place each day, unless there is need 
for an additional rescue dose post-escalation. 
 
6.5 Rescue Dose 
If, between scheduled doses, a child has a single score of >12, a rescue dose may be administered at the 
discretion of the treating physician. The rescue dose will be same as the previous dose. A rescue dose 
must be given at least 1 hour after and 1 hour before the next scheduled dose.   
 
6.6 Weaning 
The initiation of weaning can take place as soon there are 48 hours of stability without dose advancement. 
 
 
Doses will be weaned when the sum of the previous three scores is <18 and no single score is >8.   
 
 
Dose reductions will occur at a rate of 15% per wean until reaching the bottom dose (< initial dose). 
 
 
After bottom dose is reached, next weaning step is from q8 to q12 hours, followed by a step from 


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q12 to q24 hours.   
 
 
If the sum of the previous three scores is > 28 and at the discretion of the treating physician, the 
standing dose will revert to the previous dose or dose interval at which symptoms were controlled.   
 
Weaning is expected to take place during daylight hours when the primary team is present, but dose 
adjustments can take place on evenings and nights.  Only one wean of dose will take place each day.  A 
rescue dose may be administered at the discretion of the treating physician during the weaning period if a 
single score > 12.  A rescue dose during the wean will be the same as the previous dose.  The administration 
of a rescue dose in the weaning period will not trigger a dose escalation. 
 
6.7  Buprenorphine Dose Cessation and Observation 
The cessation dose of buprenorphine is at or below the initial dose. Following wean of interval at the bottom 
dose, buprenorphine dosing will cease. Infants will be observed in an inpatient setting for at least 2 days 
following last dose, during which time scoring of NAS symptoms will continue. A rescue dose after cessation 
of therapy may be given at the discretion of the treating physician for any score of >12. The amount of drug 
administered will be the last dose the patient had received. If a post cessation rescue dose is given, patients 
must be observed at least 1 day following the last rescue dose. 
 
6.8 Maximum Dose and Use of Adjunctive Phenobarbital 
Rescue doses of buprenorphine cannot be given when at maximum dose of 25 mcg/kg. Maximum dose will 
be defined by the actual weight at the time of dose administration. When the maximum dose of 
buprenorphine (75 mcg/kg/day) has been achieved, phenobarbital will be initiated with a loading dose of 
20 mg/kg followed by 5 mg/kg/day. If symptoms of NAS are not controlled with phenobarbital 5 mg/kg/day, 
this can be titrated up by the treating physician to a serum concentration of 20-40 mg/dL.  If symptoms are 
not controlled at 5 mg/kg/day, the attending physician may adjust the dose clinically as needed, with or 
without the use of phenobarbital therapeutic drug monitoring. 
 
Treatment with adjunctive phenobarbital will continue for at least two days. When buprenorphine has been 
weaned to at least 50% of the maximal dose and the sum of the previous three scores is <18 and no single 
score is >8, the attending physician will decrease the phenobarbital dose to 2.5 mg/kg/day.  The 
buprenorphine dose will not be changed when phenobarbital is weaned. The half-life of phenobarbital in 
neonates decreases from 115 hr after 1 week to 67 hr after 4 weeks.38   As such, phenobarbital will be 
continued for three dose or interval titrations.  When the sum of the previous three scores is < 18 and no 
single score is > 8, the attending physician may discontinue phenobarbital.  The buprenorphine will not be 


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weaned on the step when phenobarbital is discontinued.   
 
6.9 Study Data 
The following elements will be collected in the study data base: 
 
mode of birth 
 
gestational age 
 
gender 
 
Apgar scores 
 
NAS scores 
 
birth weight 
 
daily weight  
 
daily intake (cc/kg/day) and type of feed 
 
stool number and characteristics  
 
head circumference 
 
concomitant medication 
 
urine drug screen results 
 
dates and times of primary treatment and 
phenobarbital (if applicable) 
 
medical record number 
 
adverse events 
 
respiratory patterns 
 
Maternal elements to be collected include: 
 
opioid (methadone, buprenorphine, or other) dose 
 
urine drug screen 
 
tobacco use (none, <5 cigarettes/day, >5 cigarettes/day) 
 
concomitant medication during gestation 
 
medical record number 
 
date of birth  
 
6.10 Blood Samples for Pharmacokinetics 
Pharmacokinetic samples will be drawn on all patients randomized in the trial.  Capillary blood samples will 
be drawn by heel stick with a goal volume of 0.4 ml blood into a lithium heparin tube.  An outline of a 
sampling schedule is listed below.  In light of the sparse sampling regimen, some allowance for variation 
from this schedule is anticipated to reflect feeding and sleeping schedules for the child.  Wherever possible, 
pharmacokinetic samples will be paired with a standard of care blood draw.  A description of blood 
processing is outlined in Appendix 3. Where possible, blood draws would be 2 or 3 samples after an 
individual dose. 
 
One or two samples collected for pharmacokinetic analysis may be retained to examine ethanol 
pharmacokinetics for infants on maximum dose buprenorphine and phenobarbital.  This will help establish 
the total ethanol exposure following buprenorphine administration, and differentiate from ethyl and non-
ethyl alcohol generated by normal metabolic processes in non-ethanol exposed infants.  


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Table 9: Schedule of Pharmacokinetic Blood Draws 
 
Week 1 
Peak within 24 hours of initiation of therapy 
 
Peak and trough surrounding single dose x 2 
 
Single mid-interval dose 
Weeks 2 onward 
Peak and trough surrounding single dose 
 
Single mid-interval dose 
Dose Cessation 
Single sample between 12-24 hours after final dose 
Periods of Co-administration of phenobarbital 
Peak and trough surrounding single dose every three 
days 
 
6.11 Efficacy 
Length of treatment and length of stay will be collected in units of days. A day is defined as calendar day 
(rather than 24 hour blocks). 
 
6.12 Safety  
The safety and tolerability of sublingual buprenorphine will be evaluated by tabulating adverse events.  
Summary statistics will be used to describe relative rates in major organ systems. 
 
6.13 Urine Samples for Metabolite Analysis 
Urine collections will take place while on treatment every 5-7 days (or within on day of treatment cessation). 
Urine will be collected by means of absorbent cotton balls in the diaper. These will be squeezed into 
collection tubes. A description of urine processing is outlined in Appendix 3. Due to the difficulty of reliably 
collecting urines from infants, and the role of this assessment as an exploratory goal, failure to collect urine 
will not be considered a protocol deviation or violation. 
 
6.14 Blood Samples for Pharmacogenomics 
A single 0.2-0.4 ml whole blood sample is collected in a lithium heparin tube.  This sample will be collected 
prior to the initiation of therapy.  If this is not possible, the sample can be collected at any time post 
randomization.  Wherever possible, pharmacogenetic samples will be paired with a standard of care blood 
draw.  A description of blood processing is outlined in Appendix 3.  Alternatively, DNA can be obtained 
through the use of a cheek swab. 
 


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7 
STATISTICAL/ANALYTICAL METHODS AND POWER ANALYSIS 
 
7.1 Pharmacometrics 
The population PK/PD data will be analyzed using nonlinear mixed-effect modeling with the NONMEM 
software system (Version VI, Level 1.1, GlobalMax LLC, Hanover, MD, USA) with the PREDPP model 
library and NMTRAN subroutines.  Sparse datasets for buprenorphine will also be analyzed using advanced 
modeling software (metrumrg package on RStudio, www.R-project.org) to better support modeling and 
simulation efforts. Based on established population PK models, parent-metabolite relationship will be used 
to further understand buprenorphine disposition characteristics and inter-individual and residual variability 
in the study population. Model selection criteria will be based on diagnostic plots (predicted versus observed 
concentrations, residuals versus predicted concentrations, weighted residual versus predicted 
concentrations), reasonable parameter estimates, precision of the parameter estimates, random residual 
variances, and objective function values. To discriminate between competing models, a decrease in the 
OFV > 10.83 will be considered significant (p < 0.001). 
 
Developmental changes in newborns with NAS will be evaluated using NONMEM and SIMCYP (Version 
8.1, SIMCYP Inc, Sheffield, UK).  Simulation will be performed based on the best model selected which 
provides accurate and precise estimates of inter-subject variability and the mean parameter values. The 
simulation would provide initial dose strategy for drug treatment and allow Baysian feedback analysis for 
dose individualization. 
 
7.2 Power Analysis 
No formal power analysis is performed. This analysis is primarily descriptive and will build upon existing 
buprenorphine neonatal models. 
 
7.3 Efficacy, Safety and Pharmacogenetics 
Efficacy, safety, and pharmacogenetic analysis are expected to be exploratory and descriptive. There will 
be no power analysis for these endpoints. Pharmacogenetic analysis will primarily be to correlate externally 
identified variants which may impact buprenorphine pharmacokinetic disposition. Pharmacogenetic 
analysis may also assist in assessing the biologic basis for extreme outliers of buprenorphine concentration. 
 
8 
SAFETY PARAMETERS 
There are anticipated to be few mechanism-based risks specific to opioid treatment outside of theoretical 


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risks of respiratory depression or excessive sedation. A symptom-driven dose titration serves to minimize 
risks of over-, or under-treatment with opioids. This approach in standard of care treatment of the neonatal 
abstinence syndrome is very effective in maintaining drug dose within a therapeutic window. All infants will 
be monitored until stabilization in a high acuity of care setting on 24-hour telemetry monitoring of heart rate 
and respiratory function. Treatment of other emergent adverse events, whether judged to be drug related 
or not, will be managed by the neonatology staff of the neonatal intensive care unit (NICU). The NICU has 
24-hour senior level physician coverage and access to all subspecialty consultants. The case mix includes 
a wide spectrum of illness through critical care. The staff is able to manage, jaundice, vomiting, seizures, 
and infections. 
 
8.1 Blood volume 
No more than 12 ml of blood will be drawn over the course of the study.  This represents a maximum, and 
not the typical amount drawn.  This will include study-related blood draw as well as clinically indicated 
collection.  
 
Table 10: Blood Volume for Study Participants 
 
Procedure 
Research 
Related? 
Total 
Number of 
Collections 
Blood (mL) 
per Test 
Total Blood 
(mL/test) 
Newborn  Hematology/chemistry 
No 
1 
0.8 
0.8 
PKU screen 
No 
1 
0.4 
0.4 
Pharmacogenetic sample 
Yes 
1 
0.4 
0.4 
Buprenorphine assay 
Yes 
20* 
0.4 
8.0* 
Maximum amount of blood drawn per female 
patient  
 
10.6* 
Circumcision blood loss (estimated) 
 
0.2 
Maximum amount of blood drawn per male 
patient 
 
10.8* 
* maximum 
 
8.2 Stopping Rules 
No further enrollment will take place following a SAE judged to be probably or definitely related to study 
treatment. Following a related SAE, the independent safety monitor will review the adverse event and 
assess investigator designated causality. The safety monitor can request pharmacokinetic analysis for the 
affected infant if there is concern that the event was exposure related. Depending upon the clinical situation, 
options could include 1) continuation of study treatment with or without dose adjustment, 2) transition from 
buprenorphine to open label morphine, 3) transition from an opioid to phenobarbital monotherapy, or 4) 
cessation of all abstinence pharmacotherapy. This decision will be a consensus approach with the 


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investigator, with the input of the IRB in case of conflict between investigators and the safety monitor.  
 
If an infant is withdrawn from the study, treatment will follow clinician guidance and will not be protocol-
driven. However, such infants will be followed and will be included in safety analysis. There is no 
prespecified stopping rule for trial cessation. There is no predefined interim look for safety or efficacy. 
 
8.3 Data Safety Monitoring Plan 
An independent medical monitor will evaluate each serious adverse event judged by the investigator to be 
possibly, probably, or definitely related to study drug. The monitor will provide recommendations to the 
investigators. 
 
8.4 Certificate of Confidentiality 
A certificate of confidentiality will be obtained prior to enrollment of any protect to protect privacy of neonates 
and their mothers.   


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 APPENDIX 1: NAS SCORING SYSTEM  
Scored Elements 
 
Signs and Symptoms  
Score 
Crying: Excessive high pitched 
Crying: Continuous high pitched  
2 
3 
Sleeps < 1 hours after feeding 
Sleeps < 2 hours after feeding  
Sleeps < 3 hours after feeding 
3 
2 
1 
Hyperactive Moro Reflex 
Markedly Hyperactive Moro Reflex 
1 
2 
Mild Tremors: Disturbed 
 
Moderate-Severe Tremors: Disturbed 
1 
2 
Mild tremors: Undisturbed 
Moderate-Severe Tremors: Undisturbed 
1 
2 
Increased Muscle Tone 
1-2 
Excoriation (Indicate specific area): 
1-2 
Generalized Seizure (or convulsion) 
8 
Fever > 37.3 C (99.2 F) 
1 
Frequent Yawning (4 or more successive times) 
1 
Sweating 
1 
Nasal Stuffiness 
1 
Sneezing (4 or more successive times) 
1 
Tachypnea (Respiratory Rate >60/mm) 
2 
Poor feeding 
2 
Vomiting  (or regurgitation) 
2 
Loose Stools 
2 
Failure to thrive (Current weight > 10% below birth 
weight 90% BWT=_______ 
(record weight in score box 1 x day) 
2  
Excessive Irritability  
1-3 
Total Score 
 
Unscored Elements 
 
Convulsions 
Present/absent 
Fever > 38.4 C (101.2 F) 
Present/absent 
Mottling  
Present/absent 
Excessive sucking 
Present/absent 
Watery Stools 
Present/absent 
Projectile vomiting  
Present/absent 
Retractions 
Present/absent 
Nasal flaring 
Present/absent 
Myoclonic jerks 
Present/absent 


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APPENDIX 2:  PREPARATION OF BUPRENORPHINE STOCK SOLUTION AND 
STABILITY 
 
 
Stability 
of 
Stock 
Buprenorphine 0.075 mg/mL 
Composition of neonatal stock solution 
 
One 0.3 mg ampule buprenorphine [Buprenex 0.3 mg/ 1 ml (Reckitt 
Benckiser) or generic buprenorphine for injection] 
 
Ethanol to bring to final concentration of 30% (1.26 mL of 95% ethanol USP) 
 
Simple syrup USP(Sucrose, Purified Water and 0.1% Sodium Benzoate) to 
bring to 4 mL total volume [Humco or equivalent] 
0.3 mg buprenorphine per vial * 4 mL -1 (final volume) = 0.075 mg/mL  
 
7 days 
 
 
 


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APPENDIX 3:  PROCESSING OF PHARMACOKINETIC AND PHARMACOGENETIC 
SAMPLES 
Buprenorphine and its metabolites are stable in frozen plasma at -20 C for at least 6 months.39 In urine, 
there is stability for 16 hours at 22 C, 72 hr at 4 C and through 3 freeze/thaw cycles.40  
 
Pharmacokinetic Serum Samples 
Samples will be obtained by capillary heel stick into lithium heparin pediatric tubes (BD Microtainer, Ref # 
365971 or equivalent).  A goal of 400 microliters should be collected.  Blood is spun at 3,000 RPM on a 
refrigerated tabletop centrifuge for 10 minutes, and plasma transferred to storage tubes and frozen at -20 
C.  Blood from an indwelling catheter can be used if one is present for medical care unrelated to the 
treatment of NAS. 
 
Pharmacokinetic Urine Samples 
Volume of urine will be recorded, as well as time of start and stop of urine collection. Uncentrifuged urine 
from the collection bag will be transferred to a polypropylene tube and frozen at – 20 C. 
 
Blood for DNA  
Blood for DNA analysis will be collected by capillary heel stick into an uncoated capillary pediatric tube.  
Blood can also be collected in tubes containing anticoagulants.  
 
 


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9 
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