A Randomized Controlled Study of Stochastic Vibrotactile Stimulation for Neonatal Abstinence Syndrome: Therapeutic Efficacy and Neurobehavioral Outcomes
Phase: NA
Conditions: Neonatal Abstinence Syndrome
Sponsor: Elisabeth B Salisbury

NCT02801331 Study Protocol and Statistical Analysis Plan 
 
 
Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
 
 
Principal Investigator: Elisabeth B. Salisbury, PhD 
 
Therapeutic Management and Neurobehavioral Outcomes of Neonatal Abstinence 
Syndrome 
 
Study Protocol and Statistical Analysis Plan v.051518 
 
Funding: R01 DA042074 (Title of Grant: Stochastic vibrotactile stimulation: A non-
pharmacological intervention for abstinence and drug withdrawal in newborn infants) 
 
Document Date 12/07/20 

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
 
 
GENERAL INFORMATION 
 
 
Name and address of the sponsor of the study 
National Institutes of Health 
National Institute on Drug Abuse (NIDA) 
6001 Executive Boulevard Room 5213, MSC 9561 
Bethesda, MD 20892-9561 
 
Project officer: Ann Anderson, M.D. 
 
Name and address of the persons authorized to sign the protocol and 
amendments (by site) 
University of Massachusetts Medical School:  
Elisabeth B Salisbury, Ph.D. 
Department of Pediatrics 
55 Lake Avenue North S5-827 
Worcester, MA 01655 
 
Name and address of study monitor:  
 
Name, title, address and telephone number(s) of the medical expert for the trial: 
Alan Picarillo, M.D. 
Medical Director, NICU 
Henrico Doctor’s Hospital 
Sheridan Children’s Services of Virginia 
1602 Skipwith Road 
Richmond, VA 23229 
Alanpicarillo@schr.com 
508-887-5710 
 
Name and title of the investigator(s) and sub-investigators responsible for the 
trial with address and phone number(s)   
 
Elisabeth B Salisbury, Ph.D. 
Research Associate Professor 
University of Massachusetts Medical School 
Department of Pediatrics 
55 Lake Avenue North S5-827 
Worcester, MA 01655 
 
Elisabeth.Salisbury@umassmed.edu 
508-856-8627 
Debra Bogen, M.D.  
Associate Professor 
University of Pittsburgh 
Department of Pediatrics 
3414 Fifth Avenue 
Pittsburgh, PA 15238 
 
Bogendl@upmc.edu 
412-692-6937 
Name and addresses of the clinical laboratories and/or other institutions involved 
in the trial 
1. University of Massachusetts Medical School 
2. University of Pittsburgh 

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
 
Approved modifications not specifically noted in protocol v05.15.18 
 
 
 
 
Date 
Modification summary 
Modification summary 
Modification summary 
 
 
 
 
6/8/18 
Incorporate home visits for outcomes 
assessments/alternate contact 
Add “Ages and Stages” to 
follow up assessments 
Practical extension for signed 
consent (~30 hrs post birth)  
6/27/19 
Clarification of prisoner exclusion as 
per Prisoner Certification OHRP  
OHRP acknowledgment of 
Prisoner Certification 
(8/1/19) 
 
3/13/20 
As per UMCCTS_IRB Covid-19 study 
restrictions, halt enrollment, all in-
person bedside studies, all in-person 
study visits; followup via phone; 
adhere to state and site safety 
requirements. 
 
 
8/20/20 
State and respective site/Institutional 
Covid-19 safety protocols to resume 
in-person studies; adhere to state and 
site safety protocols; hybrid followup. 
 
 
12/7/20 
Closed enrollment due to 
unanticipated move of PI, required 
study close-out at primary Institution, 
and untimely reduction in study 
personnel.  
 
 
 
 
 
 

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
 
Table of Contents 
 
 
1  
BACKGROUND .................................................................................................................................. 1 
1.1 
TRIAL OBJECTIVES .......................................................................................................................... 1 
1.1.1 
Specific Aims ........................................................................................................................... 1 
2 
SUMMARY OF PROTOCOL .............................................................................................................. 2 
2.1 
BRIEF DESCRIPTION OF THE PROTOCOL (STUDY DESIGN) .................................................................. 2 
2.1.1 
Investigational Device. Stochastic Vibrotactile Stimulation (SVS) .......................................... 2 
2.1.2 
Study Design/Type .................................................................................................................. 2 
2.1.3 
Study Site ................................................................................................................................ 3 
2.1.4 
Study Duration ......................................................................................................................... 3 
2.1.5 
Randomization......................................................................................................................... 3 
2.2 
PRIMARY AND SECONDARY OUTCOMES ............................................................................................ 4 
 
Table 1. Primary and Secondary Endpoints ............................................................................ 4 
 
Table 2. Neurobehavioral Assessments ................................................................................. 5 
2.3 
INCLUSION/EXLCUSION CRITERIA ..................................................................................................... 6 
2.3.1 
Inclusion Criteria ...................................................................................................................... 6 
2.3.2 
Exclusion Criteria..................................................................................................................... 6 
2.4 
SAMPLE SIZE AND POWER CALCULATIONS ........................................................................................ 6 
2.4.1 
Specific Aim 1 .......................................................................................................................... 6 
2.4.2 
Specific Aim 2 .......................................................................................................................... 6 
2.4.3 
Specific Aim 3 .......................................................................................................................... 7 
3 
TRIAL MANAGEMENT ....................................................................................................................... 7 
3.1 
LIST OF PARTICIPATING ENROLLING CLINICS OR DATA COLLECTION CENTERS ...................................... 7 
3.2 
PROJECTED TIMETABLE ................................................................................................................... 8 
 
Table 3. Timeline of Benchmarks ............................................................................................ 8 
3.3 
TARGET POPULATION DISTRIBUTION  ................................................................................................ 8 
 
Table 4. Demographic Characteristics of Regional Maternal Population................................ 8 
4 
DATA MANAGEMENT AND STATISTICAL ANALYSIS PLAN ........................................................ 9 
4.1 
DATA ACQUISTION AND TRANSMISSION ............................................................................................. 9 
4.1.1 
Specific Aim 1 .......................................................................................................................... 9 
4.1.2 
Specific Aim 2 ........................................................................................................................ 10 
4.1.3 
Specific Aim 3 ........................................................................................................................ 11 
4.2 
DATA ENTRY METHODS ................................................................................................................. 12 
4.3 
DATA ANALYSIS PLAN .................................................................................................................... 12 
4.3.1 
Overview ................................................................................................................................ 12 
4.3.2 
Specific Aim 1 ........................................................................................................................ 13 
4.3.3 
Specific Aim 2 ........................................................................................................................ 13 
4.3.4 
Specific Aim 3 ........................................................................................................................ 14 
5 
QUALITY ASSURANCE ................................................................................................................... 14 
5.1 
PROCEDURES IN PLACE TO ENSURE THE VALIDITY AND INTEGRITY OF THE DATA ............................... 14 
5.2 
PROCEDURES TO GUARANTEE THE ACCURACY AND COMPLETENESS OF THE DATA, DURING DATA 
 
COLLECTION, ENTRY, TRANSMISSION AND ANALYSIS ....................................................................... 15 
5.3 
MONITORING MISSING DATA ........................................................................................................... 15 
 
 
6 
REGULATORY ISSUES ................................................................................................................... 16 
6.1 
REPORTING SERIOUS ADVERSE EVENTS (SAE) AND SUSPECTED ADVERSE REACTIONS (SAR) ............. 16 
6.1.1 
Definitions .............................................................................................................................. 16 
6.1.2 
Adverse Event Follow-Up ...................................................................................................... 17 

 
 
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6.2 
REPORTING OF IRB ACTIONS TO NIDA ............................................................................................. 17 
 
6.3 
REPORTING OF CHANGES OR AMMENDMENTS TO THE PROTOCOL .................................................... 17 
6.4 
TRIAL STOPPING RULES ................................................................................................................. 17 
6.5 
DISCLOSURE OF ANY CONFLICT OF INTEREST (COI) IN THE DSMP...................................................... 18 
7 
TRIAL SAFETY ................................................................................................................................. 18 
7.1 
POTENTIAL RISKS AND BENEFITS FOR PARTICIPANTS ....................................................................... 18 
7.1.1 
Potential Risks ....................................................................................................................... 18 
7.1.2 
Potential Benefits .................................................................................................................. 18 
7.2 
COLLECTION AND REPORTING OF AES AND SAES ............................................................................. 19 
7.3 
MANAGEMENT OF SAES OR OTHER STUDY RISKS ............................................................................. 19 
 
8 
TRIAL EFFICACY ............................................................................................................................. 19 
8.1 
PLANS FOR INTERIM ANALYSIS OF EFFICACY DATA .......................................................................... 19 
9 
DSM PLAN ADMINISTRATION ....................................................................................................... 20 
9.1 
RESPONSIBILITY FOR DATA AND SAFETY MONITORING PLAN ............................................................. 20 
9.2 
FREQUENCY OF DSMB REVIEWS ..................................................................................................... 20 
9.3 
CONTENT OF THE DSMB REPORT.................................................................................................... 20 
9.4 
DSM BOARD PLAN ......................................................................................................................... 21 
 
 
 
 
 

 
 
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List of Abbreviations 
 
 
COI 
 
Conflict of Interest 
 
DSMB  
Data Safety Monitoring Board 
 
DSMP  
Data Safety Monitoring Plan 
 
EMSM 
External Medical Safety Monitor 
 
IRB 
 
Institutional Review Board 
 
NAS   
Neonatal Abstinence Syndrome 
 
PI 
 
Principal Investigator 
 
REDCap 
Research Electronic Data Capture 
 
SAE  
Serious Adverse Events 
 
SAR  
Suspected Adverse Reactions 
 
SCC  
Standard Clinical Care 
 
SVS  
Stochastic Vibrotactile Stimulation 
 
 

 
 
Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
 
1 
BACKGROUND 
 
Neonatal Abstinence Syndrome (NAS) refers to a variety of withdrawal symptoms, 
particularly prevalent in newborns with opioid exposure. Clinically significant 
neurobehavioral symptoms include pathophysiological cardio-respiratory instabilities, 
gastrointestinal dysfunction, hypersensitivity, and sleep disruption. There is a critical 
need to develop non-pharmacological interventions for managing withdrawal in 
newborns to reduce withdrawal symptoms, facilitate weaning, decrease 
pharmacotherapy, and provide additional intervention for infants in whom 
pharmacological treatment is insufficient. Growing research suggests the importance of 
sensory tactile stimulation for promoting physiological maturation, brain development, 
and stability of function, and for improving behaviors implicated in intrauterine drug 
exposure. Evidence supports that low-level, stochastic (random) stimulation can 
promote stability in destabilized biological systems, including improved transduction of 
cutaneous mechanoreceptors in animals, sensory perception in adults, and improved 
cardio-respiratory function in premature infants. Our recent pilot data suggests that 
acute presentation of low-level stochastic vibratory stimulation (SVS) delivered through 
a uniquely-constructed crib mattress improves physiological function in drug-
withdrawing infants. We hypothesize that stochastic resonance may affect 
somatosensory and vestibular systems by facilitating more accurate detection of 
sensory inputs (e.g., touch, auditory) and increase neural stability. For example, SVS 
may stimulate pressure receptors to improve vagal tone and cardiac activity, and 
impinge upon respiratory oscillators to enhance respiratory function. The main objective 
of this proposal is to test whether early intervention (initiated within 24 hours post birth) 
and daily administration of SVS reduces withdrawal and improves neurobehavioral 
outcomes. 
 
1.1 
Trial Objectives 
This study investigates Stochastic Vibrotactile Stimulation (SVS) complementary to 
standard of care for treating NAS. Using a specially-constructed crib mattress we will 
determine if SVS reduces symptoms and duration of NAS and improves long term 
outcomes in intrauterine opioid-exposed newborns. Findings from this study will 
elucidate whether SVS has potential as a therapeutic treatment for drug-exposed 
newborns to reduce symptomatology, facilitate weaning and minimize hospitalization, 
with implications for better regulation of systems and improved developmental 
outcomes. 
 
 
1.1.1. Specific Aims. The three areas to be investigated in this project are: 
 
Specific Aim 1. Determine the efficacy of SVS as a non-pharmacological 
therapy complementary to standard clinical care (SCC) for reducing severity and 
duration of opioid withdrawal in newborns compared to SCC alone. Quantify 
clinical variables: NAS severity/administration of treatment, treatment days, days in 
hospital, velocity of weight gain, cumulative morphine dose, and longitudinal 
assessment of movement activity. 

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
 
Specific Aim 2. Examine physiological responses to SVS compared to SCC at 
two stages of withdrawal severity. Measure cardio-respiratory stability, temperature 
regulation, and movement activity. 
 
Specific Aim 3. Compare neurobehavioral outcomes in fetal drug-exposed 
infants between infants who received SVS and those who received SCC. Examine 
longitudinal outcomes assessments at 1 month, 6-months and 1 year to test whether 
early intervention with SVS compared to SCC improves physical, social, emotional and 
cognitive development.   
 
2 
SUMMARY OF THE PROTOCOL 
 
2.1 
Brief Description of the Protocol (Study Design) 
The proposed experiments aim to examine whether SVS, using a specially-designed 
crib mattress, has potential as a complementary treatment of NAS. We will determine if 
SVS reduces NAS severity (administration of treatment/treatment days), cumulative 
morphine dose and days in hospital, reduces specific physiological markers of 
withdrawal (excessive movement and cardio-respiratory instabilities), and improves 
neurodevelopment outcomes in the first year of life.  
NOTE:  All changes to the protocol must be approved by NIDA prior to implementation. 
 
2.1.1. Investigational Device. Stochastic Vibrotactile Stimulation (SVS). The 
infant’s crib mattress will be replaced with a specially constructed mattress (non-
commercially available) to provide gentle vibrations and sounds during mattress 
stimulations. The mattress is embedded with mechanical actuators that provide whole-
body SVS (30-60Hz; ~10-12µm RMS). Co Fab Design, LLC will construct the 
mattresses and drivers as per the design documents furnished under Confidentiality 
Disclosure Agreement (CDA; University of Massachusetts Medical School/Wyss 
Institute-Harvard University patent: PCT/US2015/021999) for research purposes only as 
per the licensed mattress assembly and electrical assembly and verification 
documentation; device components may be modified with improved technologies that 
provide equivalent mattress output to help ensure consistency of mattress integrity over 
time. Engineers from the Wyss Institute and the University of Pittsburgh will provide 
assistance in the build to ensure it performs as per the original patent documentation.  
2.1.2. Study Design/Type. This study is a randomized, placebo-controlled, 
parallel group clinical trial. Eligible patients will be randomized into one of two groups in 
a 1:1 ratio, matched for gender, to either (1) SVS or (2) SCC: 
 
1) SVS. Experimental Intervention: Newborn infants at-risk for NAS due to opioid 
exposure in utero randomized to this arm will receive daily intervals of continuous SVS 
(ON) and no SVS (OFF) throughout hospitalization, starting within 30-hrs post birth. An 
automated control box will be set to deliver continuous alternating 3-hr cycles of 
ON/OFF intervals. A stimulation period will always be followed by an interval of no 
stimulation; in any 24-hr period an infant will not receive more than a total of 12 hrs of 
stimulation (should the infant remain in the crib throughout an entire 24 hr period). 
Notably, infants are not always in their crib and it is not feasible to provide round-the-
clock research staffing to monitor when the infant is in or out of the crib (e.g., being held 

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
by caregiver, fed, in motorized bedside glider – all part of the standard of care). The pre-
programmed 3-hr duty cycle, 24/7, affords opportunity to capture periods when the 
infant is in the crib, and also conforms to routine timing of medication. Periods of 
stimulation will be complementary to standard of clinical care (e.g., clinically-determined 
pharmacological management; routine holding by caregiver or hospital-issued 
motorized glider; breast and/or bottle feed). A bedside log will indicate periods the infant 
is in the crib, being held, or placed in hospital-issued gliders/motorized seats. Infants will 
be scored for severity of withdrawal using standardized, modified Finnegan scoring 
system by clinical-care nurses per routine clinical care throughout hospitalization, and 
may receive pharmacological treatment as per standard care determined by the 
medical-care team at the respective institution. 
 
2) SCC. No Intervention: Standard of Clinical Care (SCC). Newborn infants at-
risk for NAS due to opioid exposure in utero randomized to this arm will be enrolled 
within 30-hours post birth and receive standard of care (e.g., clinically-determined 
pharmacological management; routine holding by caregiver or hospital-issued 
motorized glider; breast and/or bottle feed). Infants will be issued a hospital crib 
mattress. A bedside log will indicate periods the infant is in the crib, being held, or 
placed in hospital-issued gliders/motorized seats. Infants will be scored for severity of 
withdrawal using standardized, modified Finnegan scoring system by clinical care 
nurses per routine clinical care throughout hospitalization, and may receive 
pharmacological treatment as per standard care determined by the medical-care team 
at the respective institution. 
 2.1.3. Study Site.  Studies will be conducted at the UMass Memorial Healthcare 
Neonatal Intensive Care Unit (NICU), Continuing Care Nursery (CCN), and Newborn 
Nursery (NN) – referred to as UMass - and at the Magee-Women’s NICU and Well-
Baby Nursery, and Mercy Hospital, of the University of Pittsburgh Medical Center – 
referred to as UPitt - where infants receive round-the-clock medical care. Studies for 
Aim 1 and Aim 2 will be performed at the infant's hospital bedside, outcome 
assessments for Aim 3 will be performed at respective hospital inpatient (if infant still 
hospitalized) and outpatient facilities.  
 
 
 
2.1.4. Study Duration.  Subjects will participate in the study throughout their 
hospitalization, beginning within 30 hours post birth, and will be followed for up to 14 
months post post-hospital discharge via medical records, telephone interviews, and 
return visits for outcome assessments. 
 
 
 
2.1.5. Randomization. Random allocation of subject to treatment (SVS or SCC) 
will involve a permuted block design with random block sizes to assure equal treatment 
assignment for both treatments. We will stratify the randomization process by clinical 
site to force a balance between treatment groups and gender within each site. The 
random treatment assignments will be generated in SAS and uploaded into the IVRS 
system. The randomization process will verify patient eligibility before issuing treatment 
assignment. Treatment assignments will be in the form of mattress assignment tracked 
by the IVRS system based on admission and discharge information entered into 
REDCap (See 4.2 below).  The IVRS system can be accessed by certified study staff 

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
either through a telephone call or over the internet to a secure web site. The treatment 
assignments are recorded automatically in the REDCap system through an interface 
between the two systems and cannot be modified once imported from the IVRS system. 
The randomizations are monitored and verified by study staff on a routine basis. The 
IVRS also will monitor mattress availability and will notify study staff if a mattress of 
each type is not available for a randomization. (Maternal exposure will be stratified in 
the analysis). 
 
2.2 
Primary and Secondary Outcome Measures  
 
Table 1: Primary and Secondary Study Endpoints. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aim 1 
Primary  
Clinical 
Outcomes 
Aim 1 
 Longitudinal 
Physiological 
Outcomes 
Aim 2 
Acute 
Physiological  Outcomes 
(UMass only) 
Aim 3 
1-Year  Follow-Up 
Assessment 
Outcomes 
Outcome 
Variables 
NAS Severity 
Scores (trajectory: 
daily averages and 
max scores) 
 
Weight Gain/ Head 
Circumference 
(trajectory: daily 
measures) 
 
Pharmacotherapy: 
admin, type, dose 
(cumulative 
dose/normalized 
for body weight) 
 
Hospital Duration: 
Day of life infant is 
discharged from 
hospital (length of 
stay) 
Movement Activity:  
12 and 24 hr 
assessments 
actigraphy (averages: 
trajectory; frequency; 
index of sleep) 
 
 
Movement Activity 
(frequency and duration; 
histograms): Index of 
irritability and sleep 
disruption/fragmentation  
 
Cardio-Respiratory control 
(mean/histograms: 
respiratory rate, frequency 
distribution; heart rate, 
frequency distribution) 
 
Other NAS 
Symptomatology: 
Temperature/Oxygenation 
(mean) 
Environmental and 
Family Function (1-6-
12 mo) 
 
Functional Status  
(1-6-12 mo) 
 
Neurodevelopment  
(1-6-12 mo) 
 
Behavioral and 
Emotional Status (6 
and 12 mo) 
 
Parent Intellectual 
Ability 
(1 x assessment) 
 
Brief Infant Sleep 
Questionnaire (1-6-
12mos) 

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
Table 2: Neurobehavioral Assessments. 
 
Note: 1mo, 6mo, and 12mo time points are approximate testing periods. Assessments will primarily be 
administered by Outcomes Specialist in the outpatient clinic/office or at home visits, except in 
some instances: 
3 
1) BSI and McFad questionnaires may be administered in hospital by research study staff to obtain 
baseline assessment while the infant and/or mom are still in hospital (may be performed by 
Outcomes Specialist at 1mo outpatient visit if unable to administer while in hospital).  
4 
2) GOSE-E Peds and BISQ will not be performed at the 1-month time point if the infant is 
hospitalized at timeframe of testing period; we anticipate all infants will be discharged before the 
6mos assessments.  
 
3) If study staff are unable to do assessments in person (i.e., study staff unable to schedule 
assessment when subject is in-patient, at outpatient clinic/office or home visit) the following 
questionnaires may be performed by research study staff over the phone: GOS-E-PEDI, PedsQL, 
PEDI, BISQ, Bayley S&E, BSI, McFad.  The Bayley iii measures of neurodevelopment and WASI 
cannot be performed over the phone. 
4) *WASI may be administered anytime throughout the study period by Outcomes Specialist.                   
Task (time)  
Testing Age 
Description and respondent [Child (C) or parent (P)] 
Key Variables 
Functional Status of Infant 
GOS-E Peds[59] (10’) 
1mo, 6mo, and 12mo 
The 8 GOS-E Peds categories track recovery of function between groups. 
This version includes semi-structured interview questions relevant to infants. 
Administered by Outcomes Specialist. (C, P) (Upload: Pcori-GOS).  
Category score 
(1-8) 
Pediatric Quality of Life[58] (5’) 
6mo and 12mo 
The PedsQL Parent Report for Infants is available for age ranges from 1 to 12 
months.  Scales assess physical function, physical symptoms, emotional 
function, social function, and cognitive function. Administered by Outcomes 
Specialist or Research Study Staff. (P) (Upload: Peds QL) 
Total score; 
Subscale scores 
Neurodevelopment and Sleep Status of Infant 
Bayley Scales of Infant & 
Toddler 3rd Ed.[60]  (30’) 
6mo and 12mo 
The Bayley iii measures neurodevelopment to 3 yrs. Provides measures of 
cognitive function: visual preference, attention, memory, sensorimotor, 
exploration, manipulation, concept formation. Fine and gross motor 
development are also assessed.  Administered by Outcomes Specialist. (C) 
(Upload: Bayley Record Form) 
Cognitive & Motor 
Scores; Subtest 
scaled scores 
Pediatric Evaluation of 
Disability Inventory[61]  (10’) 
6mo and 12 mo 
The PEDI Mobility domain provides a standardized assessment of mobility 
skills appropriate for children up to the age of 4 years. Administered by 
Outcomes Specialist or Research Study Staff.  (C) (Upload: Pedi Self Care 
and Mobility) 
Mobility Score 
 
Brief Infant Sleep 
Questionnaire (Sadeh, 2004) 
1mo, 6mo, 12mo 
The BISQ is a modified questionnaire that provides a general assessment of 
infant sleep behaviors. Administered by Outcomes Specialist or Research 
Study Staff.  (P) (Upload modified BISQ) 
General Sleep 
Assessments 
Behavior & Emotional Status of Infant 
Bayley Social and Emotional 
Scale[60] (10’)   
6mo and 12 mo 
The Bayley S&E measures emotional adjustment of infants and toddlers. 
Administered by Outcomes Specialist*. (P) (Upload Bayley Social and 
Emotional Scale) 
Composite Score 
Parent Intellectual Ability and Psychological Status 
Wechsler Abbreviated Scale 
of Intelligence[57]  
(20’)  
*1mo 
The WASI ii is a short and reliable measure of intelligence in clinical, psycho-
educational, and research settings and is individually administered.  2 
subtests will be used to generate a FSIQ: Vocabulary requires individual to 
define words of increasing difficulty; Block Design assesses ability to 
construct two dimensional designs from multicolored blocks.  Administered by 
Outcomes Specialist.  (P) (Upload: WASI-II) 
2-Factor IQ 
Brief Symptom Inventory-18 
1mo (baseline), 6mo, 12mo 
The BSI provides a valid assessment of adult psychiatric status, including the 
domains of depression, anxiety, and somatization. Administered by Outcomes 
Specialist or Research Study Staff.  (P) (Upload BSI) 
GSI; subtest T-
scores 
Environment and Family Function of Parent 
General Functioning Scale [66]  
(5’)  
1mo (baseline), 6mo, 12 mo 
The McFad is a subscale from McMaster Family Assessment Device 
(FAD).12-item scale is an overall measure of family functioning and has been 
shown to interact with illness severity and pediatric outcome studies using the 
FAD.  Completed at study entry, 6mo, and 12 month evaluation to track 
changes in family function over time.  Administered by Outcomes Specialist or 
Research Study Staff.  (P) (Upload: Adapt McFad v1.0) 
Total score 

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
2.3  
Inclusion/Exclusion Criteria 
 
 
A total of 230 full-term (>37wks gestational age) newborn infants exposed to opioids in 
utero will be studied over the five-year funding period: 100 at UMass and 130 at UPitt.  
 
 
 
2.3.1. Inclusion Criteria. Infant inclusion criteria include documented opioid drug 
exposure (i.e., positive toxicology screen; exposure questionnaire and medical record 
history) and comprise the general population (Worcester, MA and Pittsburgh, PA 
demographics) without restriction in regard to gender, race or socioeconomic status. 
Infants may also have additional prenatal poly-drug exposure (e.g., benzodiazepines, 
barbiturates, amphetamines, cannabinoids, alcohol, nicotine and/or caffeine). Inclusion 
of pregnant women is for the sole purpose of obtaining consent to study the infant post-
delivery, and to review infant and maternal medical records. Pregnant women are 
included because we will be recruiting pregnant women who are at risk for delivering 
infants with NAS due to drug exposure in utero. Prenatal consents are needed to help 
expedite feasibility of study of infants soon after delivery. Infants will not be studied in 
utero, but will only be studied after delivery.  
 
 
 
2.3.2. Exclusion Criteria. Subjects with clinically significant fetal anomaly, 
congenital abnormality, adverse pregnancy outcome, hydrocephalus or intraventricular 
hemorrhage >grade 2, seizure disorder not related to drug withdrawal, clinically 
significant cardiac shunt, anemia (hemoglobin<8g/dL), requires mechanical respiratory 
support or is being treated for MRSA or infection at the time of the study will be 
excluded, or other medical condition aside from NAS will be excluded. Informed consent 
will be obtained from parent(s) or legal guardian of all participants.  
 
2.4 
Sample Size and Power Calculations 
For all Aims there is sufficient sample size to detect clinically meaningful differences 
with 90% power, described below: 
 
 
 
2.4.1. Specific Aim 1. We use the Finnegan NAS score as the primary outcome 
for this aim. From Nayeri et al. [70] and our own pilot data, the Finnegan NAS score in 
opioid-exposed infants had a SD of 2.0-2.5. Assuming a standard t-test with a two-sided 
alpha level of 0.05 for the unadjusted comparison of the Finnegan scores at a particular 
time point with the more conservative standard deviation (SD.=2.5), the sample size of 
115/group can detect a difference of 1.1 with 90% power. Taking into account the 
repeated measures of the Finnegan NAS score, assuming intra-infant correlations of 
0.5-0.7, we will have 90% power to detect a difference of 0.80-0.95 in a mixed effects 
model for the overall (i.e., across time) treatment group coefficient. With a mixed effects 
model, we will also add covariates as described above to determine an adjusted 
treatment effect. We expect that this model may have even more power than described 
here due to the partitioning of the overall variance among the covariates. Because 
infants are hospitalized and under observation until release, we expect only minimal 
attrition and loss of information. 
 
 
 
2.4.2. Specific Aim 2. We use Movement as primary outcome for this aim. 
Based on our preliminary data in 26 NAS infants (OFF: mean movement 40% of 
condition time, SD=10%; ON: mean movement 26% of condition time, SD=9%) and 

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
assuming a two-sided paired t-test at alpha=0.05 for the unadjusted treatment effect, we 
estimate 25 infants per group will give us 90% power to detect a reduction of 7% in 
movement between the two treatment groups (a relative reduction of about 20% from 
40% in OFF to 33% in ON) with a conservative SD of 10% (from the pilot study).   
 
 
 
2.4.3. Specific Aim 3.  We use Bayley-III as primary outcome for this aim. We 
anticipate an attrition rate of ~40% in the 1-year follow-up assessments.  Assuming a 
sample size of 60 children/group at 1 year with a two-sided standard t-test at 
alpha=0.05 and a SD of 14 for the Bayley-III cognitive composite scale, [71] we will 
have 90% power to detect a difference of 8.5 (or about a 12% difference) between the 
two groups at 1 year of age. The other Bayley scales have similar SDs, so the results 
will be similar. For a longitudinal analysis of the Bayley-III cognitive composite scale 
over the follow-up visits (1, 3, and 12 months of age), we will use a mixed effects model 
as above with months of age as the time metric in the model. Assuming the same 
sample size with intra-child correlations of 0.5-0.7 for a mixed effects model with a two-
sided test for the treatment group coefficient at alpha=0.05, we will have 90% power to 
detect a treatment effect of 6.8-7.4 (depending on the correlation) using the treatment 
group coefficient. We can also add covariates to this model to estimate an adjusted 
treatment effect.  
 
 
Each child will be classified as impaired or not based on the results of the battery of 
tests given over one year.[69] Assuming a worse-case scenario (in terms of SD of a 
proportion) of 50% impairment in the SCC group, with 60 children/group we will have 
90% power to detect an unadjusted absolute improvement of 28% (50% vs. 78%) or a 
relative improvement of 56% in the SVS group with a z-test with a two-sided alpha 
=0.05. For an adjusted estimate of the improvement in percent impairment at one year, 
we will use a logistic model with other covariates added. For a longitudinal assessment 
of impairment, we will use a GEE longitudinal logistic model with the same approach for 
model building as above.  
 
5 TRIAL MANAGEMENT 
 
3.1.  
List of Participating Enrolling Clinics or Data Collection Centers 
1. University of Massachusetts Medical School: 
 
1) University of Massachusetts Memorial Hospital: 
 
 
a) Faculty and Resident Outpatient Obstetrical Clinics 
 
 
b) NICU Prenatal-NAS Clinic 
 
 
c) Newborn Nursery 
 
 
d) NICU/CCN 
 
2) University of Massachusetts Children’s Center 
a) Pediatric Unit/Outpatient Outcomes Assessment Facilities 
2. University of Pittsburgh 
 
1) University of Pittsburgh Medical Center and Magee Women’s Hospital of 
UPMC: 
 
 
a) Outpatient Obstetrical Clinics 
 
 
b) Pregnancy Recovery Center 

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
 
 
c) Newborn Nursery/Well-Baby Nursery 
 
 
d) NICU 
 
     2) Mercy Hospital at UPMC 
 
 
a) NICU 
   
3.2.  
Projected Timetable 
Table 3. Timeline of Benchmarks. 
 
 
3.3.  
Target Population Distribution (e.g, Women, Minorities, etc) 
The proposed study requires involvement of human subjects, specifically infants, for the 
purpose of investigating the therapeutic efficacy of SVS for reducing symptomatology 
and pathophysiological instabilities associated with neonatal abstinence and drug 
withdrawal, and for improving neurobehavioral outcomes. We will attempt to recruit 
subjects who are male or female, and from all ethnic backgrounds. We will not exclude 
subjects for any reason based on race, sex, religion, ethnic background or national 
origin. The racial mix of the Worcester, MA and Pittsburgh, PA regional areas are 
identified in Table 4. We expect to be able to do the same for the proposed study with 
the caveat that the proportions of minorities will reflect the approximate subpopulation 
proportions of patients admitted to UMass and UPitt with intrauterine opioid exposure.  
 
Benchmarks 
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
Estimated Enrolled Subjects UMass/UPitt (230 
total: 100UMass; 130UPitt) 
25/22 
25/36 
25/36 
25/36 
  
Data Safety and Monitoring Board: Bi-annual 
reports 
X 
X 
X 
X 
X  
Monthly Meetings with Research Personnel 
X 
X 
X 
X 
X 
Investigator Site Visits 
X 
X 
X 
X 
X 
Aim 1 and Aim 2: Newborn In-hospital Studies:  
 
 
 
 
 
Demographic/Medical Histories; Mattress 
SVS/SSC (daily); Actigraph (daily); 2 full 
physiology studies (10-15/yr) 
X  
X 
X 
X 
X 
Aim 3: Outcomes Studies 
X 
X 
X 
X 
X 
Telephone Interviews; Outpatient Outcomes (3 
sessions) 
  
  
  
  
  
End of Year Report: 
 
 
 
 
 
Deliver up-to-date data base (demographic, 
medical, actigraph, outcomes testing); Deliver 
copy of study logs; Summary Report by site PIs 
X 
X 
X 
X 
X 
Investigators Present Preliminary Data at 
Scientific Conference/s 
  
  
X 
X 
X 
Data Collection Complete 
  
  
  
Newborn 
Studies 
Outcomes 
Testing 
Final data sets delivered to UMass 
biostatisticians; PIs submit final site reports: study 
enrollment and attrition for each arm of study; 
Final Analysis and Writing 
  
  
  
  
X  

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
Table 4. Demographic Characteristics of Regional Maternal Population. 
 
 
 
 
 
 
 
 
4. DATA MANAGEMENT AND STATISTICAL ANALYSIS PLAN 
 
4.1.  
Data Acquisition and Transmission 
4.1.1. Specific Aim 1. Determine the efficacy of SVS as a non-pharmacological 
therapy complementary to standard clinical care (SCC) for reducing severity and 
duration of opioid withdrawal in newborns compared to SCC alone - Standard 
Measurements and Recordings.  
 
1) Medical history. Prenatal exposure (e.g., prescribed maintenance therapy, 
prescription drugs and substance use during pregnancy including toxicology screens 
indicating drugs of exposure) and demographic data (gender, race, gestational age, 
birth weight, birth head circumference, delivery mode, anesthesia at delivery) will be 
obtained from infant and mother via questionnaire and medical records to help identify 
variables that may be associated with withdrawal and outcome measures. Subject’s 
medical records will be reviewed and additional history will be obtained from 
parent/guardian, including review of child’s mother medical records if the child was 
delivered at UMass. We request protected health information from general medical 
records and review of statutorily protected records at this institution to: 1) Obtain 
toxicology reports indicating drugs of exposure and other relevant records pertaining to 
NAS; 2) Make sure the child meets our inclusion criteria. An example would be to 
confirm that a child has not been diagnosed with a disorder that may cause cardio-
respiratory instability, such as intraventricular-hemorrhage greater than grade 2; 3) 
Obtain information about factors that may affect responses we observe during 
stimulation. For example, pregnancy or delivery complications, exposure to drugs in 
utero, or prescribed medications that may alter breathing and heart rhythms. We 
request to review both the child’s and mother’s medical records for information from 
cardiac studies, nursing and respiratory therapy notes, clinical monitor information, 
discharge summaries, EEG/EMG studies, laboratory results, operative procedures, 
conclusive pathologies, clinical problem list, and pulmonary, radiology and rehabilitation 
information. There will be 1-year follow up on study infants through medical record and 
telephone interview. Data will be entered by a research investigator via secure 
password protected computer into REDCap database (REDCap Consortium, Vanderbilt 
University) – see 4.2 below Data Entry Methods. 
 
 
 
2) Chart Review/Bedside Log. NAS severity scores. The infant’s clinical-care 
nurses at each site are routinely trained on the NAS assessment tool (modified 
Maternal Race  
UMass (%) 
UPitt (%) 
African American 
5.3 
19.7 
Hispanic or Latino 
10.5 
1.1 
Asian 
4.7 
2.4 
Caucasian 
78.8 
75.2 
Native American 
0.4 
0 
Two or More Races 
2 
1.6 

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
Finnegan Scale)[63] as part of clinical education; this helps ensure reliability of scores. 
Nurses score the infants’ withdrawal severity ~every 3-4 hrs to assess changes in 
central, autonomic, vasomotor and gastrointestinal function. Daily NAS scores, weight 
(gain/loss; trajectory), head circumference, routine feed type (formula or breast milk), 
pharmacological management (medication, dose normalized for body weight), and birth 
date and date of hospital will be obtained from medical and/or nursing chart review. A 
computerized and/or paper log (de-identified, subject id only) will be kept by the infant’s 
bedside to record when the infant is in the crib, and nursing/parent interventions (e.g., 
feeds, diapering, caregiver cuddling, and placement in motorized swings). This provides 
some indication of the infant’s routine clinical care since investigators cannot be at the 
bedside 24/7. A separate log kept by investigators will be used to record pre-
programmed time onset and offset of SVS (i.e., to verify daily automated SVS coinciding 
with log indicating when infant is in the crib to receive the intervention). Data will be 
entered by a research investigator via secure password protected computer into 
REDCap database. 
 
 
 
3) Movement Activity. Movement periods will be assessed via actigraphy, a 
simple non-invasive measurement using a wireless, lightweight sensor worn around the 
infant’s limb (Respironics®). The sensor is ~1.5”x1” and held in place with a soft foam 
tapeless wrap (Posey®). Actigraph sensors applied to the infant’s limb will continuously 
record the frequency of movements throughout the duration of the infant’s 
hospitalization, starting within 24-48 hrs post birth. This will allow measurement of 
frequency of leg movements (index of irritability, sleep fragmentation, wake and 
quiescence (index sleep) throughout hospitalization).[46, 47] Data will be recorded in 1-
min epochs to evaluate for movement frequency (index of activity) and quiescence over 
12h and 24h intervals and/or during periods when infants are documented in the crib 
(mattress on or off). Digitized signals will be stored on electronic data base. Data will be 
analyzed via computerized programs, stored in excel spreadsheets, and entered by a 
research investigator via secure password protected computer into REDCap database. 
 
 
 
4.1.2. Specific Aim 2. Examine physiological responses to SVS compared to 
SCC at two stages of withdrawal severity – Standard Measurements and Recording.  
 
 
 
Changes and relationships among physiological signals will be quantified in a 
sub-population of study infants at UMass. For each session, physiological signals will be 
recorded continuously for ~6-8 hrs using proprietary acquisition system. Respiratory 
inductance plethysmography will be used to measure infant’s breathing (Somonstar®); 
infant’s abdominal muscle movement will provide detection of interbreath intervals 
(index of respiratory stability) and respiratory rate. Electrodes over the skin surface of 
the chest will be used to record electrocardiographic activity (ECG; Embla®) to allow for 
detection of cardiac R-R intervals (index of interbeat variance and heart rate). A probe 
attached to the infant’s foot will measure arterial-blood oxygen concentration (Masimo®). 
Quality of the plethysmographic activity characterized in the pulse signal will also allow 
for identification of movement period duration. Movement frequency will be assessed 
with actigraphy using a wireless sensor worn around the infant’s limb (Respironics®). 
Infant axillary temperature will be measured continuously with a sensor placed under 

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
the infant’s armpit or back (Physitemp®). Environmental changes in sound intensity and 
light level will be measured with meters placed in the crib near the infant’s head 
(Extech®). Overt behavioral data will be recorded using sound-video camera with a 
wide-angled lens.  
 
 
 
Physiological data will be digitally recorded (~50-1kHz samples per channel) 
using an acquisition system that directly obtains signals from the NICU bedside monitor 
(Philips®; Wyss Institute, Harvard University) or via an independent system (Embla®). 
These systems enable fully synchronized recordings of physiological signals, 
audiometry, photometry and digital video images. Comments regarding routine nursing 
assessments and other relevant information (e.g. feeding, pharmacological dosing) will 
be typed and time stamped along with the physiological data stream. Acitgraph activity 
will be digitally recorded independent of the full-acquisition system. All signals, video 
images and germane data (e.g., medical histories of infant and mother, NAS severity 
assessments) will be stored on electronic data base. Investigators will also manually 
record relevant study information (timing and mode of experimental conditions, nursing 
assessments, feeds, medications etc) stored in the electronic data base.  
 
 
 
Data is analyzed via proprietary software and via advanced computational 
models of analysis developed for this study. Final outputs will be stored on password 
protected computers in excel data bases and will be entered by a research investigator 
via secure password protected computer into REDCap database. 
 
 
 
4.1.3. Specific Aim 3. Compare neurobehavioral outcomes in in the first year of 
life between infants who received SVS and those who received SCC – Standard 
Measurements and Recordings. 
 
 
 
1) Follow-up Chart Review and Telephone Interview. For a period of up to 14 
months post hospital discharge we will review hospital medical records for inpatient and 
outpatient visits (if the infant is treated at UMass or UPitt) for information related to 
outcomes for neonatal drug exposure. We will also follow-up for 14 months post-
hospital discharge with phone-call questionnaires (approx. every other month) to help 
identify outcomes associated with infants requiring prolonged pharmacotherapy and 
those discharged without medication, and to determine if there are differences in 
outcomes in infants treated with SVS vs SSC. Data will be entered by a research 
investigator via secure password protected computer into REDCap database. 
 
 
2)Anthropomorphic 
Examination. 
Infant 
weight, 
height, 
and 
head 
circumference are measured in the delivery room and recorded in medical record 
throughout hospitalization. Data will be entered by a research investigator via secure 
password protected computer into REDCap database. 
 
 
3) Neurobehavioral Assessments. Outpatient assessments will be conducted 
at 1 month, 6 months and 12 months (see Table 2). Data will be entered by a research 
investigator via secure password protected computer into REDCap database. 
 

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
4.2 
Data Entry Methods 
The data for this study will be recorded in a REDCap database (REDCap Consortium, 
Vanderbilt University) in the secure regulated environment (rStats) at the University of 
Massachusetts Medical School. This Unix-based environment is not accessible from 
outside of the medical school and only medical school staff with IRB approval are 
assigned an account in this environment. We will program the system for a single entry 
with validation rules for validity, consistency, and normal range values at the time of 
entry and comprehensive edits through multivariable edit approaches conducted after 
the data have been submitted to the main data base. Edit queries will be resolved by 
clinic staff with corrections posted to the database through the REDCap system, which 
enforces an audit trail for all changes. 
 
The main study database will be stored on a secure server in the University of 
Massachusetts HIPAA-compliant data center with daily back-up. REDCap will be used 
within the rStats environment to protect any PHI/PII data that are collected as part of the 
study. We will strive to minimize collection of such data and REDCap will be 
programmed to segregate that data from the main study data so that exports for 
analysis will be deidentified. 
 
Data will be exported from REDCap for import into the latest version of statistical 
software (e.g., SAS, SAS Institute, Cary, NC) for all analysis. All reports and analyses 
will be generated from these files using the latest version of SAS (currently SAS 9.3). 
Data files (and accompanying SAS programs) that are used for reports, presentations, 
or publication will be archived as required past the end of the study. The REDCap 
system will be programmed and maintained by study staff at the U Mass Medical School 
while data entry will be performed by research study staff at the U Mass Medical School 
and at the U Pittsburgh Medical School.  
 
To the extent possible, data from the laboratory assays will be conveyed electronically 
and uploaded directly into REDCap. Edit checks will be built into the upload process to 
identify any out-of-normal range values. Any edit queries will be forwarded to the 
appropriate laboratory for resolution. If a direct upload is not possible, a REDCap data 
entry screen will be implemented for the laboratory data. 
 
4.3.  
Data Analysis Plan 
4.3.1. Overview. Table 1 provides a summary list of outcome variables for each 
Specific Aim. Descriptive statistics will be calculated (means/SD or median/IQR) by 
treatment group. Because infants will be repeatedly observed and measured, initial 
analyses comparing outcomes between the treatment groups (SVS vs SCC) will be 
conducted using standard approaches assuming a normal distribution (i.e., two-sample 
t-test) or using non-parametric alternatives if assumption of a normal distribution is not 
appropriate (i.e., Mann-Whitney U Test). We will use mixed effect models to analyze the 
repeated measures over time. These models will estimate the trajectory of outcomes 
over time within each treatment group as affected by condition and other factors of 
interest. The time metric for these models will be hrs since birth for Aims 1 and 2 for 
each measurement so that the trajectories will relate to the same baseline 

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
measurement for all infants. Treatment group will be considered as fixed effect in the 
models, with other factors considered to be either fixed or random effects, depending on 
the nature of the factor: opioid only vs opioid+other; gender, delivery mode (vaginal or 
caesarean-section); delivery anesthetics (none vs anesthetics). Comprehensive 
histories from medical record and questionnaire will allow us to examine the influence of 
additional variables 
 
 
  
4.3.2 Specific Aim 1: We will use mixed effects models as described above to 
examine whether infants treated with SVS compared to SCC have: 1) Lower daily 
average and maximum NAS scores; 2) Less morphine requirement (primary 
pharmacological treatment for managing NAS at both sites; cumulative dose normalized 
for body weight); 3) Enhanced velocity of weight gain throughout hospitalization; and 4) 
Shorter hospitalization length of stay. A model will be fit for each outcome using 
Nagelkerke’s R2 to determine the model with the best fit using the ratio of the -2 log 
likelihoods for the model with covariates compared to the intercept-only model. Factors 
of interest will be included in the model as appropriate and interactions with treatment 
group will be tested as well. The interactions will indicate whether the treatment effect is 
the same across subgroups. Additional analyses to identify groups of infants who do 
particularly well (or poorly) with SVS will be conducted using latent class techniques, 
such as cluster analysis (for continuous variables) or latent class analysis (for discrete 
variables). The factors of interest will include: drug exposure (e.g., prescribed 
maintenance therapy, prescription drugs and illicit substance; with or without poly-drug 
use), demographic data (gender, race, gestational age, birth weight, birth head 
circumference, delivery mode, anesthesia at delivery), and feed type (formula or breast 
milk). 
 
 
Movement: Actigraphy (movement activity frequency) will be compared across days 
and between Groups using similar mixed effects models as above. The outcomes of 
interest are actigraphy throughout hospitalization to determine if SVS reduces 
movement and increases quiescence episodes over time (12 and 24 hour assessments) 
compared to SCC.  
 
  
  
4.3.3. Specific Aim 2: Study design allows systematic quantification of condition 
effects on breathing (IBI variance and respiratory rate), cardiac rhythm (R-R variance 
and heart rate), movement activity (frequency and duration), blood oxygenation 
(durations<85%), and skin temperature. Histogram of frequency-bands of cardio, 
respiratory and movement incidents will be determined. As with Aim 1, mixed effects 
models will be used to examine if SVS, within infants and between SVS and SCC 
infants: 1) Decreases irritability and sleep disruption/fragmentation indexed by 
movement frequency and duration; 2) Improves cardio-respiratory control: reduces 
bradycardia/bradypnea, 
tachycardia/tachypnea 
and 
increases 
incidents 
of 
eucardia/eupnea; and 3) Reduces other NAS symptoms: e.g., temperature; 
oxygenation. Additional computational signal analysis. We have developed novel 
statistical point process algorithms that measure cardio-respiratory dynamics and 
movement over continuous time domains.[67, 
68]The variable characteristics of 
respiratory (IBI) and cardiac (RR) signals are integrated with the dynamic characteristics 
of these signals to provide instantaneous, moving estimate of mean, variance and other 

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
dynamic measures (e.g., spectrum, poles, frequency).[68] These measures will be used 
to examine temporal dynamics of respiratory and heart rate rhythm, and explore 
corresponding physiological relationships with movement over time; e.g., Do IBI 
changes that reflect caudal brainstem function precede cortical behaviors such as 
arousal (e.g., movement)? Time series of movement periods will be analyzed using 
Wavelet derived SAP throughout stimulation ON and OFF to evaluate temporal 
dynamics including: 1) Response time for improvement in rhythm relative to the onset of 
stimulation; 2) Whether there is loss of efficacy over time (during each 30 min stimulus 
period as well as from one period to the next); 3) Whether improvement in rhythm 
persists following offset of stimulation.   
 
 
 
4.3.4. Specific Aim 3. One-Year Outcomes’ Assessment. We will use a 
general linear model approach to analyze outcomes over one year, using the same 
model building strategies described above. Some outcomes, such as the Bayley-III 
scales, are collected at multiple follow-up visits so we will use mixed effects models to 
estimate treatment effect over time and to adjust for other covariates. Impairment is 
determined based on a fairly extensive neurobehavioral test battery but the component 
test scores are highly correlated. To control for error that results from this correlation, 
we will reduce the number of tests by evaluating the domain or summary scores from 
the various instruments and use the approach of Ingraham and Aiken[69] to determine 
how many deviant scores are required to identify a child as impaired. This approach 
calculates the criteria for abnormality when employing batteries of multiple tests by 
generating probability curves for exceeding cut-off criteria by chance given certain 
criteria (e.g., an expectation that one group will show a decrement). This type of 
analysis will allow us to look at rate of impairment in young children with opioid 
exposure and assess whether SVS compared to SSC reduces likelihood of impairment. 
 
5 QUALITY ASSURANCE 
 
5.1.  Procedures in Place to Ensure the Validity and Integrity of the Data 
Quality Assurance of data entry and data management consists of a set of proactive 
tools that are implemented to increase the quality of the data processing components 
including: (1) Form design to avoid structural missingness, orphan questions, and as 
many “write-in” responses as possible; (2) Training of the data entry operators on the 
study forms so that they are familiar with the required responses; (3) Design of the data 
entry screens to look as much like the paper forms as possible; (4) Specifications of the 
data fields to reflect the nature of the data to be entered; (5) Specification of the edit 
parameters and checking algorithms so that every field is verified as completely as 
possible; and (6) Validation of the database system to certify that data entered into the 
data entry screens are accurately recorded in the databases. 
 
 
In other areas, quality assurance will be implemented in a variety of ways: (1) 
Training of the research staff on data collection techniques with periodic retraining; and 
(2) Immediate review of data collection to be sure that data collection forms are fully 
complete.  All staff will be trained on the protocol and issued certification numbers for 
the study. Staff will have to be certified in an area (such as data entry and patient 

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
randomization) before the study systems will allow them to perform those tasks. All 
study systems will require a dual level login procedure for each task.  
 
 
5.2.  Procedures to Guarantee the Accuracy and Completeness of the Data, 
During Data Collection, Entry, Transmission, and Analysis 
 
For quality control measures, regular analyses will report on: (1) Number of missing 
data items; (2) Number and type of forms that are failing edit; and (3) Distribution of 
data to look for outliers. A Quality Control report will be generated at the same time as 
the DSMB report for review by study leadership and by the DSMB. In addition to the 
quality assurance/quality control plans for data entry described above, we will select a 
10% sample of patients each quarter to review select (high-risk) data for verification 
against source documents, including patient characteristics and laboratory assay 
results. Any item discrepancies of greater than 2% will be discussed with the site data 
coordinator and retraining/additional observation instituted if required.   
 
 
Only research team members will have access to subject identifying information, 
which will be stored electronically only in the participant tracking database in the U 
Mass Medical School regulated environment. Each patient will be identified with a study 
ID number which will be used on all data collection forms. Only the participant tracking 
database will have the link between the study ID number and the PII of the patient. 
 
5.3  
Monitoring Missing Data 
Reports on missing data will be reviewed by the DSMB, including missing forms and 
missing data items. In addition, for data that are missing, we will consider appropriate 
imputation procedures, such as model-based multiple imputation, for study analyses. To 
identify spurious data, we will implement edit checks at data entry for values that are out 
of normal range, inconsistent values, and improper data entry so that most problems will 
be detected during data entry. Additional edit checks will be implemented to run when 
the data are submitted to the main study database. These will include edits across visits 
and across forms, so that large changes between visits and inconsistent responses 
between case report forms will generate an edit query. Edit queries will be forwarded to 
the appropriate clinical site coordinator for resolution through changes done through 
REDCap. The implementation of REDCap at University of Massachusetts Medical 
School has the audit trail fully implemented so that any changes to the original 
submitted data are recorded and documented. 
 
6  
REGULATORY ISSUES 
 
6.1.  Reporting of Serious Adverse Events (SAE) and Suspected Adverse 
Reactions (SAR) 
With regard to serious adverse events and suspected adverse reactions, both expected 
and unexpected and regardless of whether the SAE/SARs are considered related to the 
study intervention and/or the in utero drug exposure and subsequent NAS, they will be 
followed in a rigorous review process through the entire trial period. Clinical 
performance sites will be instructed to report all fatal events, unanticipated problems 
and other serious adverse events and suspected adverse reactions to the DSMB and 

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
IRB by secure email within 24 hours of first knowledge of the event. All SAES must be 
reported to NIDA within 72 hours. Additionally, all current study data for that particular 
subject will be entered to allow for timely review by the External Medical Safety Monitor 
(EMSM).  
 
The EMSM will closely monitor the incidence rates of all adverse events reported, 
whether serious or not, throughout the study, and will alert the DSMB if a trend is 
observed. A significant increase in the rate of adverse events in the SVS treatment 
group would be cause for concern for the safety of participants in the study. Information 
on adverse events will be presented in several ways: (1) Listings of serious adverse 
events with accompanying narrative summary by the Safety Officer with input from the 
Study PI; (2) Summaries of adverse events by body system and type of event. This 
information will be presented by blinded treatment group (i.e., SVS and SCC) to the 
DSMB for each group. In addition, the Safety Officer will be given treatment information 
in a blinded fashion, although he/she can request to be unblinded in cases where that 
knowledge could be critical. 
 
Serious adverse events should not be reported for hospitalization or prolonged 
hospitalization in the following scenarios: for a diagnostic or elective surgical procedure 
related to a preexisting condition; to allow for an efficacy measure for the study; or, for a 
planned surgical procedure that was not the result of a condition worsening due to 
participation in the study. 
 
A summary of all AEs and SAEs, a summary of all reports, and a coded list of all 
subjects who were terminated from the study due to study-related adverse events, will 
be included in reports submitted by the DSMB to the IRBs. An annual report will be 
submitted to the IRBs at all participating sites.  NIH NIDA will also receive all reports. 
 
6.1.1. Definitions. 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=56.102   
The clinical site investigator, on the basis of his or her clinical judgment and the 
following definitions, determines the relationship of the adverse event to the protocol 
intervention as one of the following:  
• Definitely: Any adverse reaction and those adverse events that cannot be 
reasonably explained by an alternative explanation, e.g., concomitant drug(s), 
concomitant disease(s). The relationship in time is very suggestive, e.g., 
improvement coinciding with discontinuation and recurrence on reinstitution.  
• Probably: An AE that might be due to the use of the study intervention. The 
relationship in time is suggestive, e.g., improvement coinciding with discontinuation. 
An alternative explanation is less likely, e.g., concomitant drug(s), concomitant 
disease(s); and, other causes have been eliminated or are unlikely.  
• Possibly: An AE that might be due to the use of the study intervention. An 
alternative explanation, e.g., concomitant drug(s), concomitant disease(s) is 
inconclusive. The relationship in time is reasonable; therefore, the causal 
relationship cannot be excluded and while other potential causes may or may not 
exist, a causal relationship to the study drug does not appear probable.  

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
 
 
6.1.2. Adverse Event Follow-Up. Subjects with adverse events (both serious 
and non-serious) will be followed as clinically indicated and no less often than specified 
by this protocol for standard follow-up of subjects enrolled in the study. At those visits, 
updated information on the adverse event will be collected and entered into the 
REDCap data capture system until the adverse event is completely resolved. 
 
6.2 
Reporting of IRB Actions to NIDA 
 
All actions of the UMMS or U Pitt IRBs related to the conduct of this study will be 
reported to the NIDA Project Officer immediately. Any additional follow-up will be 
discussed at that time.  
 
6.3 
Reporting of Changes or Amendments to the Protocol 
This study will be conducted in compliance with the protocol approved by the 
Institutional Review Board and according to Good Clinical Practice standards. No 
deviation from the protocol will be implemented without the prior review and approval of 
the IRB except where it may be necessary to eliminate an immediate hazard to a 
research subject. In such case, the deviation will be reported to the IRB as soon as 
possible. Any change or amendment to the protocol must have prior approval from 
NIDA PO. 
 
6.4 
Trial Stopping Rules 
There will be no formal statistical stopping boundaries proposed for this study, although 
the DSMB can request such boundaries be determined at any time during the study for 
both safety and efficacy (including futility). However, an apparent, consistent and 
persistent evidence of net harm that tends to overwhelm any benefit may allow for 
premature termination of the study. Continuing enrollment into each cohort will be 
determined in an ongoing basis and at periodic intervals. The DSMB will receive a 
report on all reported AEs and SAEs as well as the proportion of subjects with any 
specific event of interest. The finding of any unexpected serious adverse event 
considered to be related to study intervention in 2 of 6 patients will lead to review and 
suspension of recruitment and review of the complete data by the External Medical 
Safety Monitor (EMSM).  
 
Following the EMSM’s review, the safety report (and any comments from the 
EMSM) will be sent to the DSMB. The DSMB will make the final recommendation for 
early termination versus continuation of the study after reviewing the available data. The 
decision will be guided by safety. In addition to the planned evaluations, the EMSM and 
DSMB will receive quarterly safety summary reports of enrollment, baseline 
demographics, withdrawals from treatment and all AEs and SAEs with information on 
relation to study treatment. 
 

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
6.5 
Disclosure of any conflict of interest (COI) in the DSMP  
Conflict of Interest.  The PI (Salisbury) is a co-inventor on a patent for use of the 
uniquely constructed mattress that delivers the SVS. There is an approved mitigation 
plan in place at UMass due to a potential financial conflict of interest: 1) Dr. Salisbury 
will not be involved in enrolling or consenting clinical study participants; 2) The consent 
will convey potential financial interest in the clinical study; 3) Data analysis will be 
subject to a biannual Quality Assurance review by a suitable member of the UMMS 
human research protection program not otherwise associated with the Clinical Study. 
We will obtain required approvals for Dr. Salisbury to conduct studies at UPitt as per the 
Conflict of Interest Committee requirements at UPitt.   
 
7 
TRIAL SAFETY 
 
7.1   Potential Risks and Benefits for Participants 
7.1.1. Potential Risks 
 
There are no known risks of SVS mattress to be used in this study. While it may be 
difficult to discern whether changes in withdrawal symptoms are due to the intervention 
or to related system dysregulation of NAS, the protocol may be discontinued at any time 
if the investigators or the infant’s doctor suspects there are any adverse effects on 
breathing, heart rate, temperature, oxygenation, movement-irritability or any other 
function.  
 
 
The additional physiological recording measures to be used in this study are 
standard devices used on infants (e.g., surface sensors to record muscle activity, heart 
leads, respiratory plethysmograph belts placed around the surface of the infant’s rib 
cage and abdomen to record movement of respiratory muscles etc); they pose minimal 
risk of skin irritation from the adhesive/foam bracelets used to hold the sensors in place. 
Potential risk of infection is minimized by using primarily disposable sensors, and 
cleaning with sterilizing wipes any non-disposable sensors before and after each use. 
There is the potential risk of breach of confidentiality, but this is minimized by using 
alpha-numeric study code to identify subject data; furthermore all research related 
computers username and password protected. Names will not be used in any reports or 
publications of this study.  
 
7.1.2. Potential Benefits 
 
There are no known immediate direct benefits to the subjects or others. Although it is 
hoped that infants assigned to the SVS group may benefit from SVS if NAS symptoms 
are reduced and 1-year outcomes are improved, this will not be evident until completion 
of the study.  
 
7.2  
Collection and Reporting of AEs and SAEs 
 
 
Adverse events, as defined in the protocol, will be collected from the date and 
time of randomization to the date and time of hospital discharge as discussed above in 

 
 
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Salisbury R01 DA042074 DSM_ Protocol and SAP v051518 
Section 6.1. All adverse events will be coded using MedDRA and will be reported to the 
DSMB in tabular form organized by patient, showing the adverse event with the 
preferred term grouped within system organ class as well as relatedness to the 
treatment. Tables will show the treatment-emergent adverse events, i.e., adverse 
events that occurred after randomization or worsened after randomization. These tables 
will be reviewed at every DSMB meeting (and more frequently if requested).  
 
7.3 
Management of SAEs or Other Study Risks 
 
 
In the event of a serious adverse event, from disease or drug, the clinical 
presentation will be immediately reviewed by the study leadership. Management of the 
SAE will be chosen on the basis of the collective clinical decision-making of the 
investigators and the other physicians involved in the patient’s care.  
 
Any fatal events, unanticipated problems and other serious adverse events and 
suspected adverse reactions will be reported to the DSMB and IRBs by secure email 
within 24 hours of first knowledge of the event. Additionally, all current study data 
for that particular subject will be entered to allow for timely review by the External Safety 
Monitor.  
 
SAEs will be reported to the DSMB and IRBs as indicated above. The DSMB 
also will review tabulated summaries of SAE in the same format as AEs as well as 
listings of the details for each SAE, grouped within infants (for those infants with more 
than one). A narrative summary of the SAE and treatment for it will be included. 
 
An annual report will be submitted to the IRBs at all participating sites. A 
summary of all adverse events (AEs) and serious adverse events (SAEs), a summary of 
all reports, and a coded list of all subjects who were terminated from the study due to 
study-related adverse events, will be included in reports submitted by the DMSB to the 
IRBs. The funding institute, NIH OBA and FDA will also receive all reports.