Calibration Study of a Wearable Noninvasive Blood Alcohol Monitor
Conditions: Alcohol Drinking
Sponsor: Boston Medical Center

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CALIBRATION STUDY OF A WEARABLE NONINVASIVE  
BLOOD ALCOHOL MONITOR 
 
 
NCT: NCT03574181 
 
Date: 04/24/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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CALIBRATION STUDY OF A WEARABLE NONINVASIVE  
BLOOD ALCOHOL MONITOR 
 
 
 
ClinicalTrials.gov number: NCT03574181 
Protocol Version Number: 1.8 
Protocol Version Date: 04.24.19 
Sponsor:  NIAAA/NIH (KWJ Engineering) 
Principal Investigator:  Eric G. Devine, Ph.D. 
Phone: 617-638-7888 
E-mail: eric.devine@bmc.org 
 
CONFIDENTIAL 
 
This document is confidential and the property of Boston Medical Center.   No part of it 
may be transmitted, reproduced, published, or used by other persons without prior written 
authorization from the Principal Investogator. 

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TABLE OF CONTENTS 
1 List of Abbreviations ................................................................................................................ 4 
2 Protocol Summary .................................................................................................................... 5 
3 Background/Rationale & Purpose............................................................................................. 6 
3.1 
Background Information ..................................................................................................6 
3.2 
Rationale and Purpose ......................................................................................................6 
4 Objectives ................................................................................................................................. 7 
4.1 
Study Objectives ..............................................................................................................7 
4.2 
Study Outcome Measures .................................................................................................7 
4.2.1 
Primary Outcome Measures ...............................................................................7 
4.2.2 
Secondary Outcome Measures ...........................................................................7 
5 Study Design ............................................................................................................................. 7 
6 Potential Risks and Benefits ..................................................................................................... 9 
6.1 
Risks .................................................................................................................................9 
6.2 
Potential Benefits ...........................................................................................................10 
6.3 
Analysis of Risks in Relation to Benefits .......................................................................11 
7 Study Subject Selection .......................................................................................................... 11 
7.1 
Subject Inclusion Criteria ...............................................................................................11 
7.2 
Subject Exclusion Criteria ..............................................................................................11 
8 Study Intervention ................................................................................................................... 12 
9 Study Procedures .................................................................................................................... 12 
10 Assessment of Safety and Data Safety Monitoring Plan (DSMP) .......................................... 15 
10.1 Definitions ......................................................................................................................15 
10.2 Safety Review ................................................................................................................16 
10.3 Reporting Plans ..............................................................................................................18 
10.4 Stopping Rules ...............................................................................................................17 
11 Data Handling and Record Keeping ....................................................................................... 18 
11.1 Confidentiality ................................................................................................................18 
11.2 Source Documents ..........................................................................................................19 
11.3 Case Report Forms .........................................................................................................19 
11.4 Study Records Retention ................................................................................................20 
12 Statistical Plan ......................................................................................................................... 21 
12.1 Study Hypotheses and Proposed Analyses .....................................................................21 
12.2 Sample Size Determination ............................................................................................22 
13 Ethics/Protection of Human Subjects ..................................................................................... 23 
14 Literature References .............................................................................................................. 25 
15.  Appendix A: Schedule of Events ........................................................................................... 27 

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1 
List of Abbreviations 
 
Abbreviation 
Abbreviation definition 
Area under the concentration–time curve 
AUC 
Alcohol Use Disorder 
AUD 
Blood Alcohol Concentration 
BAC 
Blood Alcohol Level 
BAL 
Breath Alcohol Concentration 
BrAc 
Clinical Institute Withdrawal Assessment 
CIWA 
Concentration Maximum levels 
Cmax 
Columbia Suicide Severity Rating Scale 
C-SSRS 
Electrocardiogram 
ECG 
General Clinical Research Unit 
GCRU 
Repeated Measures Correlation Coefficient 
RMCC 
Time-Line Follow-Back 
TLFB 
Transdermal Alcohol Concentration 
TAC 
Time to reach the Cmax 
Tmax 
 
 

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2 
Protocol Summary 
Title: 
Calibration Study of a Wearable Noninvasive Blood Alcohol 
Monitor 
Population: 
The present study will involve 12 men and women aged 21 to 
55 who drink regularly and occasionally binge-drink.    
Women and minorities who meet the study criteria will be 
eligible to participate. No vulnerable populations are being 
targeted for inclusion in this study 
Intervention: 
Eligible subjects will receive alcohol in the laboratory setting.  
Subjects will complete a drinking session designed to raise 
BAL to 0.05 g/dL.  Data from this drinking session will be 
used to calibrate wristwatch sensors with BAL measured by a 
breathalyzer.  Subjects will return for a second drinking 
session following completion of the calibration trial.  Data 
from this second trial will be used to validate the calibration 
model.  During both drinking sessions subjects will have 
access to streaming entertainment.  BAL will be measured 
continuously with  wristwatch sensors, and every 15 minutes 
with a breathalyzer.   
Objectives: 
This NIH SBIR Phase II study addresses development of a 
new, noninvasive wrist-mounted device for measuring blood 
alcohol. This wristwatch platform with modern smartwatch 
capabilities will move the state of innovation forward in the 
noninvasive alcohol monitoring field and will contribute 
societal benefits in the form of facilitating alcohol research and 
treatment.  Additional benefits include providing blood alcohol 
monitoring to consumers interested in health and fitness, 
employer wellness programs and other medical and judicial 
system uses. If successful, the transdermal alcohol sensor 
could be used in clinical research as an objective measure of 
drinking outcomes. 
Design/Methodology: This trial is designed to generate data that will be used to build 
a model that will transform transdermal alcohol readings into 
an approximate measure of breath alcohol level.  The ultimate 
goal is to test the accuracy of a wristwatch BAL monitor 
relative to alcohol breath testing once this model has been 
completed.   An established human laboratory self-
administration procedure will be followed.  Each subject will 
complete 4 clinic visits over a period of up to 9 months  of 
participation.  Study participation is comprised of 1) a baseline 
assessment to determine eligibility 2) an alcohol self-
administration trial to develop a model for correlating 
transdermal alcohol with breath alcohol readings, 3) a follow-
up assessment to confirm eligibility to continue, and 4) an 

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alcohol self-administration trial to test the accuracy of the 
wristwatch BAL monitor .   
Total Study 
Duration: 
The entire study will take 12 months to complete. 
Subject Participation 
Duration: 
Each subject’s length of participation will be up to 9 months.   
 
3 
Background/Rationale & Purpose 
 
3.1 
Background Information 
The goal of this study will be to continue development and commercialization of a new 
noninvasive transdermal alcohol monitor developed by KWJ Engineering, Inc. The wrist-
mounted transdermal ethanol measurement system being studied in this proposal is part of the 
modern trend toward wearable and noninvasive measurements. In recent years there has been a 
growing trend in science and technology toward developing noninvasive on-body, continuous 
measurements in the management of chronic disease, monitoring the elderly, diagnostic sensing 
and other biomedical applications [1-7]. Stretchable and flexible materials for dermal sensors are 
emerging, as are new approaches to making physical and chemical measurements noninvasively 
on the skin [8-11]. KWJ engineering is an industry-leading manufacturer of monitoring sensors, 
instruments, and gas sensors designed to reduce risks to health, safety, and security in 
commercial and consumer environments.  KWJ has recently received an SBIR phase II award 
from NIAAA to continue efforts to develop a wearable transdermal sensor that monitors Blood 
Alcohol Level (BAL) in real-time.  The monitor is based on the KWJ Engineering’s printed 
electrochemical gas sensor that is able to detect ethanol concentrations in the skin.  This ethanol 
sensor is a very small, ultralow power, and highly sensitive device with very low interferences. 
In previous studies leading up to the SBIR award, KWJ Engineering has demonstrated stable and 
sensitive measurement of ethanol across human skin surrogate membranes.  This was 
accomplished with an initial prototype wristwatch device that included the ethanol sensor and 
circuitry for performing the measurement and converting data for wireless communication to a 
computer. Raw transdermal ethanol concentrations were calibrated to blood alcohol values using 
standardized ethanol solutions as a surrogate for blood alcohol concentration (BAC).  KWJ has 
demonstrated a high degree of reproducibility in measurement sensitivity across several watch 
format devices.  
 
3.2 
Rationale and Purpose  
In this proposed study, the objective is to further demonstrate the reliability of this printed 
electrochemical gas sensor in the form of a wearable device.  This demonstration of reliability 
among human subjects is an essential part of product development.  The monitor will be in a 
wristband or watch form, similar to a smartwatch. It will also have smartwatch features including 
measuring key physiological parameters (e.g., pulse) and eventually will have connectivity to 
apps on smartphones and other devices. The aim of the work is to provide a new, noninvasive 
transdermal alcohol monitor into the market. The transdermal alcohol monitoring market has few 
wearable products available and innovation has been lacking in this field. Developing a new 
wearable alcohol sensor could have many applications.  For example, people interested in health 
and fitness who want to better track their alcohol intake. This may be particularly beneficial to 

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individuals who seek to reduce the risk of alcohol use by limiting peak BAL.  This technology 
could be adapted for use in clinical trials where measurement of alcohol consumption is typically 
the primary outcome measure.  Although the current “gold standard” for measuring alcohol use 
(the TLFB method) has acceptable reliability and validity, a wristwatch might offer advantages 
over the TLFB given the potential for precision of data that cannot be achieved with the 
estimation methods used with the TLFB.  A wristwatch sensor may also offer an objective means 
of data collection that is less vulnerable to the risk of subject deception or intentional 
minimization.  Additionally, there is a certain degree of subject reactivity to completing drinking 
assessments on a weekly basis that alters the course of drinking.  If successful, this wristwatch 
may provide a means for assessing alcohol consumption without subjects reacting to the 
assessment methodology.  This technology could also be adopted in many areas including 
clinical and medical treatment, employee wellness programs, alcohol, and as part of brief 
interventions that target at-risk drinkers.    
 
4 
Objectives 
 
4.1 
Study Objectives 
 
The specific objective of this study is to determine whether the printed electrochemical gas 
sensor designed to measure BAL will be sensitive and reliable when compared to a standard 
measure of BAL taken by a breathalyzer (Intoximeter Alco-Sensor IV).  If this sensor proves 
sensitive to changes in BAL and can reliably measure BAL relative to a “gold standard” method, 
there are significant opportunities to use this technology in consumer health applications and 
clinical research.   
 
4.2 
Study Outcome Measures 
 
4.2.1 
Primary Outcome Measures 
 
The primary outcome is the correlation in estimated BAL as measured by the breathalyzer and 
the wristwatch sensor during the second alcohol self-administration trial.  BAL and wristwatch 
sensor data correlation will be analyzed by repeated measures correlation (rmcorr) analysis, as 
described in more detail in section 12. 
 
4.2.2 
Secondary Outcome Measures 
 
In addition to the determination of correlation between BAL and transdermal alcohol 
concentration (TAC) as measured by a reference breathalyzer and the developmental KWJ wrist 
device, respectively, we anticipate that Phase I of this study (the first alcohol self administration 
trial) will provide a means to determine the characteristic time lag between BAL and TAC [12] 
and furthermore allow development of a preliminary model for correcting TAC measurements 
for this lag. 
 
5 
Study Design 
 

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This is a device calibration study designed for healthy non-treatment-seeking drinkers.  The 
drinking lab portion of this study is an adaptation of an established human laboratory self-
administration procedures [13].  Subjects who consent to this study will complete two alcohol 
self-administration sessions, one in the Calibration phase (Phase I) of the study and one in the 
Validation phase (Phase II) of the study.    
 
Calibration Phase I.  The calibration phase of this study is designed to gather data to assist in 
developing an equation to account for the lag in TAC readings and transform these readings into 
an approximation of alcohol breath readings.  In this calibration phase subjects will be given a 
measured dose of alcohol to achieve a peak BAL level of 0.05 g/dL after a one hour drinking 
session.  The volume of alcohol will be calculated using an online tool developed by UW-
Madison (http://dionysus.psych.wisc.edu/WebCMS/baccalc.htm) based on a formula described 
by Watson [14].  The hour-long drinking session will be followed by a five hour observation 
period to ensure that subject reach peak TAC.  Blood alcohol level will be measured 
simultaneously using the transdermal sensors and the breathalyzer for the duration of the 
drinking period and observation period.  Breathalyzer readings will be taken every 15 minutes 
during the entire experiment and transdermal sensors will log data continuously. To ensure 
residual alcohol in subjects’ mouths does not provide a false breath alcohol reading, subjects will 
rinse their mouth twice with water after consuming a saltine cracker prior to each breathalyzer 
given while the subject is consuming alcohol.  Subjects will remain in the drinking lab for up to 
five hours to allow for measurement of the peak transdermal alcohol concentration.  Given the 
length of observation, we estimate that subjects will fully metabolize the alcohol they received 
during the calibration session and they will have a BAL of 0.00 g/dL when the calibration 
session is over.  In the event that a drinking session is halted or the subject has a very slow rate 
of metabolism, we require that subjects remain in the laboratory until their BAL, as measured by 
breathalyzer, reaches 0.04 g/dL or less. The drinking session will be video-recorded to provide a 
record of the exact timing of breathalyzer readings.  If methodology or safety issues are 
uncovered during the Phase I of this study, the protocol may be amended to address these issues 
prior to completing Phase II.   
 
 
Validation Phase II.   Data from Phase I of this study will be used to develop a model to account 
for the lag in transdermal sensor readings relative to breathalyzer readings.  Once all subjects 
have completed Phase I and the calibration model is complete, subjects will return to the 
laboratory to complete Phase II of the study. Given the expected time lag between Phase I and 
Phase II, eligibility will be re-assessed prior to the Phase II drinking session to ensure subject 
safety (see appendix A for schedule of events). If the subject remains eligible for Phase II of the 
study, the Phase II validation drinking session will be scheduled within 14 days of re-assessing 
eligibility.  During the validation drinking session subjects will be given a measured dose of 
alcohol to achieve a peak BAL level of 0.05 g/dL after a one hour drinking session.  The 
drinking period will be followed by a three-hour observation period. Blood alcohol level will be 
measured simultaneously using the transdermal sensors and the breathalyzer for the duration of 
the drinking period and observation period.  Breathalyzer readings will be taken every 15 
minutes during the entire experiment and transdermal sensors will log data continuously. To 
ensure residual alcohol in subjects’ mouths does not provide a false breath alcohol reading, 
subjects will rinse their mouth twice with water after consuming a saltine cracker prior to each 

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breathalyzer given during the drinking period.  Subjects will remain in the laboratory until their 
BAL, as measured by breathalyzer, reaches 0.04 g/dL or less.  
   
 
Subjects: Subjects will be recruited through radio advertisements, newspaper advertisements, 
study flyers, social media, and internet postings.  Interested subjects will be screened by 
telephone to determine initial eligibility prior to the baseline assessment.  
   
6 
Potential Risks and Benefits 
 
6.1 
Risks 
Physical discomforts: 
The drawing of blood may cause pain, bruising, lightheadedness, and on rare occasions, 
infection. Subjects may briefly feel the prick of the needle when it is inserted.  Subjects may feel 
dizzy or faint when blood is drawn. Trained phlebotomists will be used to minimize these risks.    
ECGs may cause discomfort and/or irritation of the skin (redness and itching) from the adhesive 
electrodes. Hair on the subjects’ chest may need to be removed in order to obtain the best 
electrical contact between the adhesive electrodes and subjects’ skin. Trained staff will be used 
to minimize these risks. 
 
Risk to recovery efforts 
Treatment-seeking drinkers will be excluded from this study to minimize the risk that drinking in 
the laboratory could worsen outcomes for a subject trying to reduce or abstain from alcohol. All 
subjects will undergo a medical screening and we will exclude subjects who have a medical or 
mental condition for which alcohol exposure in this study would be contraindicated.  All subjects 
will receive the NIAAA self-help guide Rethinking Drinking at the end of study participation 
[15].  
 
Risk of overconsumption  
To minimize the risk of subjects reaching a level of intoxication that is uncomfortable to them, 
we will remind subjects that they may discontinue study participation at any time.  Subjects who 
qualify for this study will have experience consuming alcohol at an amount similar to the dose 
chosen for this study.  Subjects will be monitored during the course of the study.  Medical staff 
will evaluate subjects and may make a determination to halt study participation if the subject 
becomes too behaviorally impaired or if there are emergent safety issues.  During the descending 
BAL period, subjects will have access to a comfortable space with entertainment (streaming 
media), snacks, non-alcoholic beverages, and a nearby bathroom.  
Subject release: 
 Subjects who have a BAL greater than .04 g/dl or who appear to be too behaviorally 
impaired to leave our research center will be asked to remain in the clinic until their 

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intoxication is reduced to a level that it is safe to discharge them from the research 
laboratory.   
 Subjects will not be released within 60 minutes of their last drink consumed to ensure 
that peak BAC has been reached prior to discharge.    
 Onsite medical supervision (study RN or GCRU RN) will be maintained while the 
subjects are in the lab until the time of discharge (<0.040 g/dL) or until they reach a BAL 
= 0.000 g/dL  
 
Risk of loss of confidentiality  
There is some risk that health information collected as part of this study could be seen by 
unauthorized individuals.  Every effort will be made to minimize this risk and protect subject 
confidentiality.  Electronic data will be housed in the REDCap data management system.  
REDCap is protected via Secure Sockets Layer (SSL) encryption that provides access restriction 
options.  Exported data from REDCap will be stored on a secure password-protected server 
behind the BMC firewall. Source and CRF binders will be stored in a double-locked area that is 
accessible to only study staff.  Subjects will be assigned a study identification number and this 
will be used to code any forms that do not require the subject’s direct identifiers (e.g., consent 
form, laboratory results, and contact information).  A linking key that associates study ID with 
direct identifiers will be stored in a double-locked cabinet accessible only by study team 
members.  Data will be stored on a password-protected computer accessible only to the study 
team.  Video of subjects during the drinking session will be stored on an encrypted drive with 
password protection.  Video files will be deleted at the end of the study.  All study staff will 
receive appropriate training for the protection of human subjects (NIH Protecting Human 
Research Participants, CITI Training). A certificate of confidentiality will be sought to protect 
subjects from disclosure under court order or subpoena.  
 
Psychiatric risk 
We do not anticipate that study procedures will have risk for psychiatric problems.  Although we 
are excluding people with suicidality, it is possible that subjects will identify suicidal ideation or 
behavior either in screening or during the study.  To minimize the risk of worsening suicidal 
thoughts and behaviors we will monitor suicidal thoughts and behaviors  using the Columbia-
Suicide Severity Rating Scale and the MINI Neuropsychiatric Interview.  Subjects with a MINI 
suicidality score greater than 8 (low risk) will be excluded.  Subjects who report any active 
suicidal thoughts or behavior as measured the C-SSRS will be excluded from participation.  In 
addition to excluding active suicidality, the MINI will be used to rule out subjects who have 
psychiatric conditions that may increase the risk of the occurrence of suicidal thoughts or 
behavior (e.g., major depression, bipolar disorder).  Assessment and scoring of suicide rating 
scales will be conducted in real-time while the subject is present.  Suicidality will be assessed by 
trained clinical staff including study MDs, a psychologist, a nurse, and a mental health counselor.  
If subjects are found to be at risk for self-harm, study staff will work with the subject to develop 
a safety plan that could include escorting the subject to the BMC ED or calling BEST.   
 
6.2 
Potential Benefits 
 

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Although there is no potential direct benefit to participation, this study presents a strong potential 
for benefit to science.  There are very few objective measures of alcohol consumption that can be 
used to determine outcomes in clinical trials for people with alcohol use disorder.  Among the 
objective measures that are available, data about drinking is limited with regard to accurate 
measurement quantity and frequency of consumption.  A wearable wristwatch that accurately 
measures BAC could be used to calculate the timing, frequency, and quantity of drinking as a 
continuous measure throughout an alcohol treatment study.  This device also has significant 
potential value as a consumer device that could be used as a tool to help people achieve a goal of 
less risky drinking.   
 
6.3 
Analysis of Risks in Relation to Benefits 
 
The most significant risk of this study is consuming alcohol.  We have chosen a dose that is 
consistent with the baseline drinking of our targeted sample, and we have included appropriate 
protections to safeguard the well-being of our subjects.  With the protections we have in place 
for all the potential risks in this study, we believe the risks of this study are well minimized.  The 
study holds significant promise for helping to develop new technology that could be used in both 
clinical trials and the consumer market.  We believe the risk/benefit ratio is favorable. 
 
7 
Study Subject Selection 
 
7.1 
Subject Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1.  21-55 years of age. 
2.  Can provide proof of age with state or federal picture ID.  
3.  Consumes an average of  ≥7 standard drinks per week (women) or ≥14 drinks per week (men) 
over the 28 days prior to consent. 
4.  Has consumed at least 4 standard drinks on a single day on at least two days in the past 28 
days prior to consent. 
5.  Has a BAL = 0.000 at time of consent.   
6.  Is able to understand and provide written informed consent. 
7.  Body weight  ≥ 120 lbs and ≤ 250 lbs 
8.  Subjects can speak and understand English 
 
7.2 
Subject Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
 
1.  Currently seeking treatment for alcohol problems or purposefully abstaining from alcohol in 
an attempt to cut back or quit drinking.  
2.  Clinical Institute Withdrawal Assessment at ≥10. 
3.  Meets DSM-5 diagnosis of current major depression, bipolar disorder, schizophrenia, 
bulimia/anorexia, dementia, or a substance use disorder other than alcohol, nicotine, marijuana, 
or caffeine 

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4.  If female, pregnant or nursing.   
5.  If female, does not agree to use an accepted form of birth control 
6.  Has medical or mental condition for which further alcohol exposure at the planned dose range 
would be contraindicated. 
7. Taking medication for which drinking would be contraindicated.  
8.  Clinically significant abnormal ECG. 
9.  AST or ALT ≥ 3x the upper limit of normal. 
10.  Current risk of suicidality. 
11.  Has taken medications that are used to treat AUD in the past 90 days. 
12.  Has received alcohol counseling or other non-pharmacologic intervention to treat AUD in 
the past 90 days. 
13.  Has urine toxicology results positive for cocaine, opioids, amphetamines, buprenorphine, 
methadone, or methamphetamines. 
14.  Smokes greater than 5 cigarettes per day.  
15.  Unable to comfortably abstain from nicotine for a period of 8 hours.  
15.  Wearing cologne, perfume, aftershave or any other scented oil or alcohol-based beauty 
product on the day of the Alcohol Lab Visit. 
16.  Has dietary restrictions that would preclude participating. 
 
8 
Study Intervention 
This is a non-interventional study. 
 
9 
Study Procedures 
Study Overview: Each subject will complete 4-5 clinic visits over a period of up to 9 months of 
participation.  Study participation is comprised of a baseline assessment, Phase I BAL calibration 
session, Phase II eligibility determination session, and Phase II BAL validation session.    
 
Baseline assessment 
Consenting subjects will undergo a general medical screen, including medical history physical 
examination.  Drinking will be assessed using the TLFB [16], alcohol withdrawal using the 
Clinical Institute Withdrawal Assessment [17], and suicidality using the Columbia-Suicide 
Severity Rating Scale (C-SSRS) [18].  Exclusionary mental health conditions will be assessed 
using the MINI Neuropsychiatric Interview for DSM-5 [19].  Subjects will undergo urine 
toxicology and a urine pregnancy test for women of child bearing age. The baseline assessment 
may be completed in one or two visits.   
 
Phase I BAL Calibration session:  
Subjects will return to the laboratory within 14 days after completion of the baseline assessment 
to complete the Phase I BAL calibration session.  For safety reasons, subjects will be asked to 
arrange transportation plans for this study visit.  The alcohol lab visit is divided into four phases: 
1) Screening, 2) Zero BAL observation, 3) Alcohol Administration, and 4) Observation.  
 
1) Screening.  Eligibility to continue in the study will be confirmed in a brief screening session.  
Subjects will undergo vital signs, alcohol breath test, urine drug screening, assessment of 
concomitant medications, assessment of alcohol withdrawal, urine pregnancy testing (for 
women), adverse event assessment, suicidality screening, and assessment of drinking since the 

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baseline.  Blood alcohol level must be 0.000 to continue with the study procedures.  Subjects will 
be excluded if urine toxicology results positive for cocaine, opioids, amphetamines, 
buprenorphine, methadone, or methamphetamines.  Subjects will also be excluded if any 
concomitant medications that present safety issues for drinking have been started since the 
baseline assessment.   Subjects will be excluded if the CIWA ≥10 or if the C-SSRS indicates any 
current suicidal ideation or behavior.   
 
2) Zero BAL observation.  Subjects will be escorted from the Clinical Studies Unit to the General 
Clinical Research Unit (GCRU) for the remainder of the alcohol lab visit.  The room in the 
GCRU that will be used is carpeted and furnished with a lounge chair, side table, table lamp and 
television which allows access to popular streaming entertainment (e.g., Netflix, YouTube, and 
HBO-GO). A small unobtrusive camera is mounted in one corner to allow for monitoring 
without study staff being present in the room. During the Zero BAL observation period (and all 
subsequent phases in the GCRU) study staff and subjects will be instructed not to use any 
alcohol-based sanitizing hand cleaners due to the potential for interference with the BAL 
wristwatch sensor.  During the Zero BAL session study staff will fit the BAL wristwatches on 
subjects and begin a 1-hour period of baseline monitoring of a zero BAL.  This observation 
period will be used to demonstrate that the BAL wristwatches do not provide false positive 
readings under zero BAL conditions.  Study staff will measure BAL every 15 minutes during this 
60-minute observation period using a breathalyzer.  Subjects will have access to streaming 
entertainment during this period, but will be asked to limit use personal electronics for the 
duration of the zero BAL session.   
 
3) Alcohol Administration.  After 60 minutes of Zero BAL observation the drinking self-
administration session will begin.  At the start of the alcohol administration session the subject 
will be given a pre-determined volume of alcohol designed to raise BAL to  0.05 g/dL.    The 
volume of alcohol will be calculated using an online tool developed by UW-Madison 
(http://dionysus.psych.wisc.edu/WebCMS/baccalc.htm) based on a formula described by 
Watson59.  The hour-long drinking session will be followed by a five hour observation period to 
ensure that subject reach peak TAC.  Blood alcohol level will be measured simultaneously using 
the transdermal sensors and the breathalyzer for the duration of the drinking period and 
observation period.  Breathalyzer readings will be taken every 15 minutes during the entire 
experiment and transdermal sensors will log data continuously. To ensure residual alcohol in 
subjects’ mouths does not provide a false breath alcohol reading, subjects will rinse their mouth 
twice with water after consuming a saltine cracker prior to each breathalyzer given while the 
subject is consuming alcohol.  Subjects will have access to streaming entertainment during this 
period, but will be asked to not use personal electronics for the duration of the self-
administration session. This drinking session will be video recorded to confirm exact times of 
BAL readings taken with the breathalyzer.  Subjects will remain in the laboratory until their 
BAL, as measured by breathalyzer, reaches 0.04 g/dL or less.  
  
4.  Observation.  Subjects will remain in the drinking lab for five hours of observation following 
alcohol administration.  Breathalyzer readings will be taken every 15 minutes during the 
observation and transdermal sensors will log data continuously.  Data from this observation will 
be used to develop a model that adjusts for the lag in peak TAC relative to measured BAL using 
a breathalyzer.  Subjects will continue to have access to streaming entertainment and will also 

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have access to any personal electronic devices for this phase.  Subjects will consume crackers 
and water just prior to the first breathalyzer reading during this phase.  This observation period 
will be video recorded to confirm exact times of BAL readings taken with the breathalyzer.  
Subjects will be monitored during the observation until their blood alcohol level is ≤ 0.0 g/dL 
and they are not behaviorally impaired to leave.  Four hours after consuming alcohol subject will 
be given a light meal that is approximately 375 calories.  Study staff will assess intoxication, 
sedation, and adverse effects during this observation period.  Subjects will also have access to 
snacks (e.g. chips, granola bars) and non-alcoholic beverages if the time needed to reach ≤ 0.04 
g/dL exceeds the 5-hour observation period. Subjects will be required to have a plan for 
transportation home that does not involve driving or riding non-motorized transportation (e.g., 
bike, scooter).   
 
Phase II eligibility determination session 
Once all subjects have completed phase I of the study and the model for adjusting TAC readings 
has been developed, subjects will be invited back to the lab to complete phase II of the study.  
Eligibility will be re-assessed to ensure subject safety prior to completing the second drinking lab 
(see appendix A for schedule of testing events).  
 
Phase II BAL validation session 
Within 14 days of subjects completing the Phase II eligibility Determination session, subjects 
will return to the clinic to complete the Phase II BAL validation session.  This second alcohol lab 
visit is divided into the same four phases as the Phase I BAL calibration session: 1) Screening, 2) 
Zero BAL observation, 3) Alcohol Administration, and 4) Observation.  The procedures for this 
second alcohol lab session are the same with a few exceptions:  
 
1) Subjects will be wearing second generation wristwatch sensors. 
2) TAC readings will be converted into estimated breathalyzer BAL readings based on the model 
developed in Phase I. 
3) The observation period will last only 3 hours (or longer of needed for BAL to reach ≤ 0.04 
g/dL).   
 
If a subject completes Phase I and is unable to complete Phase II for any reason, replacement 
subjects will be recruited to complete Phase I and II consecutively. It is estimated that 36 
subjects will be consented to yield 12 subjects that will complete Phase I and 9 subjects that will 
complete Phase II.  Based on past experience with subject attrition, it is estimated that 33% of 
the Phase I subjects will be replaced at the time of phase II.  Given the sample size requirements 
for this study are 9 subjects to complete both trials, the total sample size is estimated to be 12 
subjects taking into account the possibility that three subjects will be lost to follow-up between 
trials one and two.  If subjects are lost, when these subjects are replaced they will complete both 
the calibration session and validation session over the period of approximately 60 days.      
 
Subject compensation 
Subjects will be compensated up to $340 for completion of all study activities.  In addition to 
reimbursements for each study visit, subjects who complete all study visits will receive a 
completion bonus at the end of the study. If at any time subjects are discontinued from the study 
during a visit, subjects will be paid a portion of the payment based on time completed (e.g., 1 

Calibration Study of a Wearable Noninvasive Blood Alcohol Monitor  
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hour completed of two-hour visit = 1/2 of payment). Note there is an exclusion for payment due 
to UDS+ at the baseline.   
 
Subjects will receive the following reimbursements: 
Baseline assessment  
 
 
$40 
Phase I BAL Calibration session 
 
$100 
Phase II eligibility determination session 
$40 
Phase II BAL validation session 
 
$100 
Completion Bonus 
 
 
 
$60 
 
.   
 
10 Assessment of Safety and Data Safety Monitoring Plan (DSMP) 
 
10.1 
Definitions 
 
The following definitions will be used in the assessment of safety: 
 
Adverse Event (AE) is any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the subject’s participation in the research, 
whether or not considered related to the subject’s participation in the research. Participation in 
the research does not include the time between Phase I and Phase II of the study.  Subjects will 
not be monitored for adverse events in the time between Phase I and Phase II as there are no 
study activities during this time period.   
 
Serious Adverse Event (SAE) is any adverse event that  
(1) results in death; 
(2) is life-threatening; 
(3) results in inpatient hospitalization or prolongation of existing hospitalization; 
(4) results in a persistent or significant disability/incapacity; 
(5) results in a congenital anomaly/birth defect; or 
(6) based upon appropriate medical judgment, may jeopardize the subject's health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition (examples of such events include allergic bronchospasm requiring intensive 
treatment in the emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse).  
 
Life-threatening means that the event places the subject at immediate risk of death from the 
event as it occurred.  
 
Unanticipated Problem is defined as an event, experience or outcome that meets all three of the 
following criteria:  
 
is unexpected; AND 
 
is related or possibly related to participation in the research; AND 

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 
suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.  
 
Possibly related means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research 
 
Unexpected means the nature, severity, or frequency of the event is not consistent with either: 
 the known or foreseeable risk of adverse events associated with the procedures involved in 
the research that are described in (a) the protocol–related documents, such as the IRB-
approved research protocol, any applicable investigator brochure, and the current IRB-
approved informed consent document, and (b) other relevant sources of information, such 
as product labeling and package inserts; or 
 the expected natural progression of any underlying disease, disorder, or condition of the 
subject(s) experiencing the adverse event and the subject’s predisposing risk factor profile 
for the adverse event. 
 
10.2 
Safety Review 
 
Both the risks listed in Section 6.1 and unknown risks will be monitored as follows:  
 
Adverse events will be monitored from the time of study consent through the end of the first 
drinking session.  Adverse events will not be monitored in the estimated 9 months between 
drinking session 1 and drinking session 2 as there are no study activities in this period.  Adverse 
event monitoring will resume when the subject returns to complete assessment prior to the 
second drinking session, and it will continue until the subject has completed the study.   
 
Adverse events will be monitored by medical staff using the “adverse events” CRF.  Adverse 
events will be assessed on the alcohol self-administration day.  If a subject has an ongoing SAE 
or unanticipated problem at the time that the subject completes all study procedures, Adverse 
Event assessment will continue until satisfactory resolution (either resolved or stabilized and is 
not expected to resolve in the near term) of the event or problem. 
 
For each recorded AE or SAE, the study MD staff or study nurse will assess expectedness based 
on the known risks of study participation.  The study MD staff or study nurse will also assess 
severity based on the following criteria: 
Mild: 
An event that is usually transient, requiring no special treatment, and does 
not generally interfere with the subject’s daily activities. 
Moderate: 
An event that interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the 
subject. The event is usually ameliorated with additional specific 
therapeutic intervention.  
Severe: 
 
An event that interrupts usual activities of daily living or significantly 
affects clinical status. The event poses a significant risk of harm to the 

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Mild: 
An event that is usually transient, requiring no special treatment, and does 
not generally interfere with the subject’s daily activities. 
subject and hospitalization may be required, and typically requires 
intensive therapeutic intervention. 
Life-threatening 
An event that puts the subject into imminent risk of death without 
intervention. 
 
Study staff will assess whether AEs and SAEs are unexpected: 
Unexpected means the nature, severity, or frequency of the event is not consistent with either: 
 the known or foreseeable risk of adverse events associated with the procedures involved 
in the research that are described in (a) the protocol–related documents, such as the IRB-
approved research protocol, any applicable investigator brochure, and the current IRB-
approved informed consent document, and (b) other relevant sources of information, such 
as product labeling and package inserts; or 
 the expected natural progression of any underlying disease, disorder, or condition of the 
subject(s) experiencing the adverse event and the subject’s predisposing risk factor 
profile for the adverse event. 
 
The study MD staff or study nurse will assess AE/SAE relationship to the study procedures 
based on the following criteria: 
 
Unrelated: 
The temporal sequence of the AE/SAE onset relative to study procedures is 
not reasonable, or there is another obvious cause of the AE/SAE. 
Unlikely: 
It is possible that the AE/SAE is related to exposure to study procedures but 
there is another more likely cause of the AE/SAE. 
Possible: 
The temporal sequence of the AE/SAE onset relative to study procedures is 
reasonable, but the AE/SAE could have been due to another equally likely 
cause. 
Probable: 
The temporal sequence of the AE/SAE onset relative to administration of the 
study procedures is reasonable, and the AE/SAE is more likely explained by 
the study procedures than by any other cause. 
Definite 
The temporal sequence of the AE/SAE onset relative to administration of 
study procedures is reasonable, the AE/SAE is more likely explained by the 
study procedures than by any other cause, and the AE/SAE shows a pattern 
consistent with previous knowledge of the risks of study procedures.   
 
 
10.3 
Stopping Rules 
 
There are no interim analyses planned that would allow for a determination of futility or 
overwhelming benefit.  Study enrollment will be suspended under the following circumstances: 

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1.  Serious Adverse Events.  Study enrollment will be suspended in the event of a single serious 
adverse event that is determined to be unexpected and at least possibly related (i.e. it is an 
Unanticipated Problem).  If suspended, study recruitment will not continue until a determination 
has been made about whether the known risks of participation have changed and the BU Medical 
Campus/Boston Medical Center IRB has made a finding that the risk/benefit ratio remains 
favorable given the possible newly identified risk.   
2.  Risk of intoxication.  Subject recruitment will also be suspended if more than one subject of 
the first ten subjects enrolled is discontinued by the investigator due to intoxication during the 
alcohol self administration trial.  Due to differences in alcohol tolerance, BAL is not a reliable 
measure of subjects potentially posing a safety risk.  Medical staff will make a subjective 
determination of risk based on the subject’s behavior.  After 10 subjects have been enrolled, the 
trial will be suspended if there are more than 10% of subjects whose participation has been 
halted by the study team due to concerns about physical safety because of intoxication during the 
alcohol self-administration trial. If suspended for this reason, the study team will consider design 
changes to reduce the likelihood of this as a potential risk to study subjects.  Recruitment would 
resume when the BU Medical Campus/Boston Medical Center IRB has made a determination 
that proposed changes to the study design have an acceptable risk/benefit ratio. 
 
10.4 
Reporting Plans 
 
The Principal Investigator at BMC/BU Medical Campus will report Unanticipated Problems, 
safety monitors’ reports, and Adverse Events to the BMC/BU Medical Center IRB in accordance 
with IRB policies: 
 Unanticipated Problems occurring at BMC/BU Medical Campus involving a fatal or life-
threatening event will be reported to the IRB within 2 days of the investigator learning of 
the event. 
 Unanticipated Problems occurring at BMC/BU Medical Campus not involving a fatal or 
life-threatening event will be reported to the IRB within 7 days of the investigator learning 
of the event. 
 Reports from safety monitors with recommended changes will be reported to the IRB 
within 7 days of the investigator receiving the report.  
 Adverse Events (including Serious Adverse Events) will be reported in summary at the 
time of continuing review, along with a statement that the pattern of adverse events, in 
total, does not suggest that the research places subjects or others at a greater risk of harm 
than was previously known. 
 Reports from safety monitors with no recommended changes will be reported to the IRB at 
the time of continuing review.  
 
11 Data Handling and Record Keeping 
 
11.1 
Confidentiality 
 
All staff will be fully trained in the procedures for protection confidential health information.  To 
maintain subject confidentiality, study data will be coded on CRFs that are identified by a subject 

Calibration Study of a Wearable Noninvasive Blood Alcohol Monitor  
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number only. Source records with identifying information and CRFs will be stored in double-
locked space with access only by authorized staff.  Data stored in the REDcap system will have 
strong protections including file encryption and password access.  Subject information will not 
be released without written permission.  Upon approval of the study by an IRB, an application 
will be filed with NIAAA for a Certificate of Confidentiality.  
 
11.2 
Source Documents 
 
Source documents in this study include: 
Laboratory test results 
Photocopies of the urine drug screening test result 
ECG tracings 
Subject locator form 
Subject contact form 
 
Data generated by the methods described in the protocol will be recorded in the subjects' source 
binder. Data may be transcribed legibly on CRFs for each subject or directly inputted into an 
electronic system or any combination thereof. 
 
11.3 
Case Report Forms 
 
The study case report form (CRF) will be the primary data collection instrument for the study. 
All data requested on the CRF will be recorded. All missing data will be explained. If a space on 
the CRF is left blank because the procedure was not done or the question was not asked, a 
written explanation will be included to detail why the data was not recorded.  If the item is not 
applicable to the individual case, a notation will be made.  All entries will be printed legibly in 
black ink. If any entry error has been made, to correct such an error, a single straight line will be 
drawn through the incorrect entry and the correct data will be entered closely to the original data. 
All such changes will be initialed and dated.  There will be no erasures or white-out on CRFs.  
For clarification of illegible or uncertain entries, the clarification will be printed near the item, 
then initialed and dated. Electronic CRFs in the REDcap system will include an audit trail.   
 
The CRFs that will be used in this study are: 
Demographics 
Concomitant Medications 
Adverse Events 
Birth Control Assessment 
Urine Drug Screening  
Vital Signs 
Blood Alcohol Level 
Time-line Follow-back 
Pregnancy test 
Birth control assessment 
Medical History 
Physical Examination 

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MINI diagnoses summary 
Medication Compliance log 
Eligibility 
ECG 
C-SSRS 
CIWA-AR 
 
 
11.4 
Study Records Retention 
Study records will be retained for at least seven years after completion of the study.  

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12 Statistical Plan 
 
12.1 
Study Hypotheses and Planned Analyses 
 
Calibration Phase I  
The objective of the Phase 1 of this study is to use data obtained from subjects who have 
consumed alcohol in a controlled laboratory setting to develop  a model of the relationship 
between BrAc and TAC measurements that will allow for the determination of estimated blood 
alcohol levels (BAL) from TAC data collected over extended periods of time.    
The results of several studies support the expectation that for most subjects  the time to reach 
peaked alcohol concentrations (Tmax)  will be greater for TAC as compared BrAc values [20-
21]. In contrast, maximal BrAc concentration (Cmax) values are expected to be smaller be for 
TAC values collected during test session as compared to those obtained for  BrAC 
measurements. Nevertheless, if TAC values detected by the test device are a directly related to 
blood alcohol levels there should be will be a strong correlation between the CMax for both TAC 
and BrAc measurements.   Therefore, we hypothesize that for correlations between Cmax values 
for TAC and BrAc values should be have an r value of 0.8 or greater. A finding consistent with 
this hypothesis will provide evidence that the test alcohol monitor is able to detect TAC levels 
that are directly related to BAL.  
Validation Phase  
Validation Phase  
TAC data collected during validation phase will be converted into predicted BAL values for 
individual subjects using the models developed in the Phase 1 of this investigation. Data 
obtained during the validation phase will be inspected to determine if there are differences in the 
sensitivity between the breathalyzer and the wristwatch sensor. Time concentration curves for 
BrAc and predicted BAL values will be produced for each subject. These curves will be 
examined to check whether there are any systematic differences between these two measures in 
the time needed to reach maximal concentration levels for each of the subjects (Tmax) and 
between the values obtained at the maximum concentration levels (Cmax). . 
Predicted BAL that will be determined from TAC data are expected to be equivalent to 
BrAc concentrations. We, therefore hypothesize that there will be a strong correlation between 
BAL and BrAc measurements obtained at the same time points for the individual subjects. The 
reference breathalyzer response is known to be linear over the range of expected blood alcohol 
levels in the study [23].  Therefore, the breathalyzer and predicted BAL values are expected to be 
linearly related to each other. To confirm the hypothesis that these values are highly linearly 
related an analysis will be conducted in which repeated measures correlation coefficient (rcmm)] 
between BrAc and BAL will be obtained. In contrast to a simple correlation analysis of data in 
which repeated measures collected from individual subjects are used, here will be no violation of 
the assumption of independence of observations when rcmm values are utilized as the measure of 
the extent of correlation between these values [Bakdash and Marrusich, 2017].   

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Data obtained in the validation phase of this study will be analyzed using the proc glm 
procedure for SAS 9.4.  This data will include values for individual subjects obtained for each 
time-point at which BrAc measurement were made and corresponding predicted BAL values 
determined for these subjects. This data will be analyzed using following general linear model:  
 
BAL= BrAc sub  
This model is equivalent to an analysis of covariance model in which subjects (sub) are a 
covariate. This model will allow for the determination of whether BrAc and BAL values are 
significantly related to one another. The correlation coefficient [rcmm] for relationship between 
BAL and BrAc will be determined using the following equation first mentioned by Bland and 
Altman [24] with sum of squares values being obtained from the results of our glm analysis:  
rcmm= square root [Sum of Squares BAL/ (Sum of Squares BAL + Sum of Squares Residual)] 
 
Since both BrAc and BAL measurements are hypothesized to be linear, the rcmm value is 
expected to be >0.80 with high correlation power.  The statistical null hypothesis is that the 
predicted BAL measurements are not related to the standard breathalyzer measurements.  The 
study is designed to maintain a probability of Type I and Type II error rates with respect to the 
null hypothesis at p<0.05. 
 
Given that BAL and BrAc are expected to equivalent it is also hypothesized that there 
will be a strong correlation between Cmax and Tmax values. Pearson correlation coefficients for 
correlation analysis between both Cmax and Tmax determined from individual subjects’ BrAc 
and BAL curves, therefore, are expected to be 0.8 or greater, with p values being less than 0. 05.  
 
 
Hypothesis 
Planned Analyses 
1. There will be a 
significant correlation 
between BrAc predicted 
BAL measures  
Repeated measures correlation analysis of wristwatch TAC 
measurements and contemporaneous BAC measurements from 
breathalyzer. 
2.  There will be a 
significant correlation 
between Cmax and 
Tmaxalues obtained for 
paired BrAc and predicted 
BAL measurements.  
Pearson correlation analysis for Tmax and Cmax values obtained 
for BrAc and predicted BAL data. 
 
We expect that the results of this study will demonstrate the effectiveness of the developmental 
wristwatch transdermal alcohol sensor.  Furthermore, these results and the developmental work 
to calibrate this wristwatch will contribute significant knowledge toward the understanding of 
reliable measurement of blood alcohol via transdermal routes. 
 
12.2 
Sample Size Determination 
 

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Power analysis: Eight concurrent readings of breathe (BAL) and transdermal alcohol 
concentration (TAC) will be obtained from the wristwatch sensor and the breathalyzer starting 
15 minutes after the start of subject alcohol consumption to the end of the 60 minute drinking 
session.  An additional 20 concurrent readings will be collected during the 5 hour observation 
period in phase I, and an additional 12 concurrent readings in the 3-hour observation period in 
phase II.  This means that a possible 28 (Phase I) or 20 (phase II) points may be available for this 
analysis if only pairs of data are used for which values for both devices exceed zero. However, 
the sensitivity of the wristwatch sensor in human subjects is currently unknown, and so fewer 
than 20 data points may be of use for our analysis.  
Data will be analyzed using a repeated measures correlation (rcmm) procedure described by 
Bland and Altman [24] and Bakdash and Marisich [25]. For the wristwatch device to be 
considered to be useful the r value for the correction between BrAc and predicted BAL measures 
must exceed 0.9. Cohen [26] defines a large effect size as being r=0.5. Bakdash and Marish 
provide power curves for the rcmm procedure. These curves indicate that for a large effect size 
(r=0.5) that the power approach 99% when  data from only 10 points are available for sample 
size of about 7.  We anticipate a repeated measures correlation value of at least 0.8 and hope to 
observe a correlation of 0.9. Bakdash and Marisich [25] indicate the degrees of freedom for 
determining rcm values can be determined using the following equation:  
Df= (Number of subjects-2) x (number of data points -1). 
The degrees of freedom can be used to determine the corresponding sample size, with the 
degrees of freedom for standard tables of power analysis being equal to N-2 (Df=N-2). Using 
this relationship we use the Proc Power procedure for Pearson correlations in SAS to determine 
the power for 21 data points collected for 9 subjects and 10 datapoints for 5 subjects. In both of 
these analyses the calculated power value was > 0.995 for rcm of 0.8 or 0.9.   
If the existence of a time lag is found that precludes the usefulness of rcm values then  Pearson 
correlations will  be determined for AUC and Cmax values. For both of these value obtained for 
the TAC-BAL data for  r=0.8, power will equal 0.82 for a sample size of 9 subjects who 
complete Phase I and Phase II.  We anticipate consenting 36 subjects to achieve a sample size 12 
randomizers and 9 completers.  
 
Given that this is a laboratory-based experiment we do not plan to conduct any planned interim 
analyses in this study. 
 
13 Ethics/Protection of Human Subjects 
 
This study is to be conducted according to applicable US federal regulations and institutional 
policies (which are based in federal regulations, guidance, and ICH Good Clinical Practice 
guidelines). 
 
This protocol and any amendments will be submitted to the Boston Medical Center and Boston 
University Medical Campus IRB, for formal approval of the study conduct. The decision of the 

Calibration Study of a Wearable Noninvasive Blood Alcohol Monitor  
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IRB concerning the conduct of the study will be made in writing to the investigator. A copy of 
the initial IRB approval letter will be provided to the sponsor before commencement of this 
study.  
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. The consent form will be submitted with the protocol for review and approval by the IRB. 
The consent of a subject, using the IRB-approved consent form, must be obtained before that 
subject is submitted to any study procedure. Consent will be documented as required by the IRB.   

Calibration Study of a Wearable Noninvasive Blood Alcohol Monitor  
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14 References 
 
1. Pantelopoulos, A. and N.G. Bourbakis, A survey on wearable sensor-based systems for health 
monitoring and prognosis. IEEE Transactions on Systems, Man and Cybernetics, Part C 
(Applications and Reviews), 2010. 40(1): p. 1-12. 
2. Allet, L., et al., Wearable Systems for Monitoring Mobility-Related Activities in Chronic 
Disease: A Systematic Review. Sensors, 2010. 10(10): p. 9026-9052. 
3. Patel, S., et al., A review of wearable sensors and systems with application in rehabilitation. 
Journal of Neuroengineering and Rehabilitation, 2012. 9: p. 17. 
4. Y. Hao, R. Foster, “Wireless Body Sensor Networks for Health Monitoring Applications,” 
Physiol. Meas., 29, R27-R56 (2008). 
5. V. Gay, P. Leijdekkers, “A Health Monitoring System Using Smart Phones and Wearable 
Sensors,” Int J. ARM, 8, 29-36 (2007). 
6. M. Chan, D. Esteve, J.-Y. Fourniols, C. Escriba, E. Campo, “Smart Wearable Systems: 
Current 
Status and Future Challenges,” Artificial Intelligence in Medicine, 56, 137-156 (2012). 
7. A. Darwish, A. E. Hassanien, “Wearable and Implantable Wireless Sensor Network Solutions 
for Healthcare Monitoring,” Sensors, 11, 5561-5595 (2011). 
8. D. H. Kim, R. Ghaffari, N. Lu, J. Rogers, “Flexible and Stretchable Electronics for 
Biointegrated 
Devices,” Annu. Rev. Biomed. Eng., 14, 113 – 128 (2012). 
9. J. R. Windmiller, J. Wang, “ Wearable Electrochemical Sensors and Biosensors: A Review,” 
Electroanalysis, 25, 29-46 (2013). 
10. C. Zuliani, D. Diamond, “Opportunities and Challenges of using Ion-selective Electrodes in 
Environmental Monitoring and Wearable Sensors,” Electrochim. Acta, 84, 29-34 (2012). 
11. A. J. Bandokar, J. Wang, “Noninvasive Wearable Electrochemical Sensors: A Review,” 
Trends Biotechnol., 32, 363 – 371 (2014). 
12.  Hill-Kapturczak N., Roache J. D., Liang Y., Karns T. E., Cates S. E., Dougherty D. M. 
Accounting for sex-related differences in the estimation of breath alcohol concentrations using 
transdermal alcohol monitoring, Psychopharmacology. 2015, 232,  115-123.  
13.  O'Malley SS, Krishnan-Sarin S, Farren C, Sinha R, Kreek MJ. Naltrexone decreases craving 
and alcohol self-administration in alcohol-dependent subjects and activates the hypothalamo-
pituitary-adrenocortical axis. Psychopharmacology (Berl). 2002 February 01; 160(1): 19-29. 
14.  Watson PE, Watson ID, Batt RD. Prediction of blood alcohol concentrations in human 
subjects. updating the widmark equation. J Stud Alcohol. 1981 July 01; 42(7): 547-556. 
15.  Rethinking drinking [homepage on the Internet]. Bethesda, MD: NIH publication. 2009. 
Available from: https://www.rethinkingdrinking.niaaa.nih.gov/. 

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16.  Sobell LC, Sobell MB. Timeline followback: A technique for assessing self-reported alcohol 
consumption. In: Litten RZ, Allen JP, editors. Measuring alcohol consumption: psychosocial and 
biochemical methods. Totowa, NJ: Humana Press; 1992. p. 41-72. 
17.  Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. Assessment of alcohol 
withdrawal: The revised clinical institute withdrawal assessment for alcohol scale (CIWA-ar). Br 
J Addict. 1989 November 01; 84(11): 1353-1357. 
18.  Oquendo MA, Mann JJ. Risk factors for suicidal behavior: Utility and limitations of research 
instruments. In: First MB, editor. Standardized Evaluation in Clinical Practice. Washington, DC: 
American Psychiatric Publishing; 2003. p. 103-130. 
19.  Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker 
R, Dunbar GC. The mini-international neuropsychiatric interview (M.I.N.I.): The development 
and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin 
Psychiatry. 1998; 59 Suppl 20: 57. 
20.  Karns-Wright TE, Roache JD, Hill-Kapturczak N, Liang Y, Mullen J, Dougherty DM 
(2017).  Time Delays in Transdermal Alcohol Concentrations Relative to Breath Alcohol 
Concentrations.. Alcohol Alcohol. Jan;52(1): 35-4 
21.  Leffingwell TR1, Cooney NJ, Murphy JG, Luczak S, Rosen G, Dougherty DM, Barnett NP. 
(2013).  Continuous objective monitoring of alcohol use: twenty-first century measurement using 
transdermal sensors. Alcohol Clin Exp Res.  Jan;37(1):16-22. 
22.  Linearity of KWJ Sensor: Carter, M.T., Wearable Noninvasive Blood Alcohol Monitor, 
Final Report on NIH SBIR Phase I award No. 1R43AA024651-01, March 30 2017. 
23.  Linearity of Intoximeter: (a)  https://www.intox.com/product/alco-sensor-iv/; (b) 
http://aviga.lt/doc/AS-IV_W.M.+PR..pdf 
24.  Bland JM, Altman DG (1995).  Calculating correlation coefficients with repeated 
observations: Part 1--Correlation within subjects.. BMJ. Feb 18;310(6977):44 
25.  Bakdash JZ, Marusich LR. (2017)  Repeated Measures Correlation. Front Psychol. 2017 Apr 
7;8:456. 
26.  Cohen, Jacob (1988). Statistical Power Analysis for the Behavioral Sciences. Routledge. 
ISBN 1-134-74270-3. 
 
 
 
 
 
 

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15.  Appendix A: Schedule of Events 
 
Basel
ine 
Phase I 
Calibration 
session 
Phase II 
eligibility 
determinati
on 
Phase II 
Validation 
session 
Clinic Visit # 
1 
2 
3 
4 
Informed Consent 
X 
 
 
 
Locator Form  
X 
 
 
 
Demographics 
X 
 
 
 
Medical History 
X 
 
X1 
 
Physical Exam 
X 
 
 
 
MINI V 6.0 
X 
 
 
 
Clinical labs 
AST, ALT 
X 
 
X 
 
Urine Drug Screen  
opioids, cocaine, 
amphetamines, 
methamphetamine, 
tetrahydrocannabinol 
(THC), barbiturates, 
oxycodone, 
buprenorphine, 
methadone and 
benzodiazepines 
X 
X 
X 
X 
Vital Signs, weight, 
Blood Alcohol Level 
X 
X 
               X 
               X 
ECG 
X 
 
 
 
Prior and Concomitant 
Meds 
X 
X 
X 
X 
CIWA-AR 
X 
X 
X 
X 
Eligibility Checklist 
X 
X 
X 
X 
Urine Pregnancy Test   
X 
X 
X 
X 
Birth control assessment 
X 
X 
X 
X 
AEs 
X 
X 
X 
X 

Calibration Study of a Wearable Noninvasive Blood Alcohol Monitor  
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C-SSRS 
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Alcohol Education 
 
 
 
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TLFB (28 day at 
baseline phase II 
eligibility visits) 
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