A Proof of Concept, Randomized, Single Center Study on Frameworks for Wearable Devices to Sense and Respond to Opioid Overdoses
Conditions: Opioid Overdose, Opioid-use Disorder, Substance Use Disorders
Sponsor: University of Pennsylvania

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A PROOF OF CONCEPT, RANDOMIZED, SINGLE CENTER, 
STUDY ON FRAMEWORKS FOR WEARABLE DEVICES TO 
SENSE AND RESPOND TO OPIOID OVERDOSES 
 
NCT ID # 834304 
01/14/2020 
 
 
 

 
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Table of Contents 
Contents 
LIST OF ABBREVIATIONS......................................................................................................................... IV 
STUDY SUMMARY ...................................................................................................................................... 1 
BACKGROUND AND STUDY RATIONALE ................................................................................................ 3 
1 INTRODUCTION ........................................................................................................................................ 3 
1.1 
BACKGROUND AND RELEVANT LITERATURE ..................................................................................... 4 
FIGURE 1: OVERDOSE PROGRESSION WITH NALOXONE INTERVENTION ....................................... 4 
FIGURE 2: OVERDOSE PROGRESSION WITHOUT NALOXONE INTERVENTION ................................ 4 
1.2 NAME AND DESCRIPTION OF THE INVESTIGATIONAL PRODUCT ................................................................. 5 
1.2.1 
Nonclinical Data....................................................................................................................... 6 
2 
STUDY OBJECTIVES ......................................................................................................................... 6 
2.1 
PRIMARY OBJECTIVE ...................................................................................................................... 6 
2.2 
SECONDARY OBJECTIVES ............................................................................................................... 6 
3 
INVESTIGATIONAL PLAN .................................................................................................................. 6 
3.1 
GENERAL DESIGN .......................................................................................................................... 6 
3.1.2 
Screening Phase ..................................................................................................................... 7 
3.1.2 
Study Design Phase ................................................................................................................ 7 
3.1.2 
Follow Up Phase ..................................................................................................................... 7 
3.2 
STUDY ENDPOINTS......................................................................................................................... 7 
3.2.1 
Primary Study Endpoints ......................................................................................................... 7 
3.2.2 
Secondary Study Endpoints .................................................................................................... 8 
4 
STUDY POPULATION AND DURATION OF PARTICIPATION ........................................................ 8 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 8 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 8 
4.3 
SUBJECT RECRUITMENT ................................................................................................................. 8 
4.4 
DURATION OF STUDY PARTICIPATION .............................................................................................. 8 
4.5 
TOTAL NUMBER OF SUBJECTS AND SITES........................................................................................ 8 
4.6 
VULNERABLE POPULATIONS: .......................................................................................................... 9 
5 
STUDY DESIGN PHASE ..................................................................................................................... 9 
5.1 
RECEIPT ........................................................................................................................................ 9 
5.2 
STORAGE ...................................................................................................................................... 9 
5.3 
BLINDING ....................................................................................................................................... 9 
5.4 
ADMINISTRATION AND ACCOUNTABILITY .......................................................................................... 9 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................... 9 
5.5.1 
Return or Destruction of Investigational Product ..................................................................... 9 
6 
STUDY PROCEDURES ....................................................................................................................... 9 
6.1.1 Screening (Parts 1 and 2) ......................................................................................................... 10 
6.1.2 Baseline Visit ............................................................................................................................. 10 
6.2 FOLLOW UP PHASE OF THE STUDY ....................................................................................................... 10 
6.3 SUBJECT WITHDRAWAL ....................................................................................................................... 10 
6.4 DATA COLLECTION AND FOLLOW-UP FOR WITHDRAWN SUBJECTS ......................................................... 10 
7 
STUDY EVALUATIONS AND MEASUREMENTS ............................................................................ 11 
7.1 
MEDICAL RECORD REVIEW ........................................................................................................... 11 
7.2 
PREGNANCY TESTING .................................................................................................................. 11 
7.3 
LABORATORY EVALUATIONS ......................................................................................................... 11 
7.4 
OTHER EVALUATIONS, MEASURES ................................................................................................ 11 
7.5 
SAFETY EVALUATIONS .................................................................................................................. 11 

 
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8 
STATISTICAL PLAN ......................................................................................................................... 11 
8.1 
PRIMARY ENDPOINT ..................................................................................................................... 12 
8.2 
SECONDARY ENDPOINTS .............................................................................................................. 12 
8.3 
SAMPLE SIZE AND POWER DETERMINATION ................................................................................... 12 
8.4 
STATISTICAL METHODS ................................................................................................................ 12 
8.4.1 
Baseline Data ........................................................................................................................ 12 
8.5 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 12 
9. SAFETY AND ADVERSE EVENTS ....................................................................................................... 13 
9.1 
DEFINITIONS ................................................................................................................................ 13 
9.1.1 
Adverse Event ....................................................................................................................... 13 
9.1.2 
Serious Adverse Event .......................................................................................................... 13 
9.2 RECORDING OF ADVERSE EVENTS ....................................................................................................... 13 
9.3 RELATIONSHIP OF AE TO STUDY .......................................................................................................... 14 
9.4 REPORTING OF ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND UNANTICIPATED PROBLEMS ............ 14 
9.5 
Follow-up reports ................................................................................................................... 15 
9.6 
Investigator reporting: notifying the Sponsor ......................................................................... 15 
10 REPORTING PROCESS ....................................................................................................................... 16 
10.1 Devices ....................................................................................................................................... 17 
10.2 Source Documents ..................................................................................................................... 17 
10.3 Case Report Forms (CRFs) ....................................................................................................... 17 
11 CONFIDENTIALITY ............................................................................................................................... 17 
12 DATA COLLECTION AND MANAGEMENT ......................................................................................... 18 
13 RECORDS RETENTION ....................................................................................................................... 18 
14 STUDY MONITORING, AUDITING, AND INSPECTING ...................................................................... 19 
15 ETHICAL CONSIDERATIONS .............................................................................................................. 19 
16 RISKS .................................................................................................................................................... 19 
17 BENEFITS ............................................................................................................................................. 19 
17.1 
RISK BENEFIT ASSESSMENT ......................................................................................................... 20 
17.2 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION .............................................................. 20 
18 STUDY FINANCES ................................................................................................................................ 20 
18.1 Funding Source .......................................................................................................................... 20 
18.2 Conflict of Interest ...................................................................................................................... 20 
19 PUBLICATION PLAN ............................................................................................................................ 20 
20 REFERENCES ....................................................................................................................................... 20 
 
 
 
 
 
 
 
 
 
 
 

 
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List of Abbreviations 
 
AE: Adverse event 
CRF: Case report form 
DOVE: Delivery of Opioid agonists for Ventilatory Emergencies 
 
 
 
 
 
 

[DOVE Device prototype] 
 
page 1 
Version 1.0 
Study Summary 
Title 
Assessing opioid overdose response framework for wearable 
medical devices  
Short Title 
DOVE 
IRB Number 
834304 
Phase 
Pilot Study 
Methodology 
Part 1- is an exploratory study in which we will be conducting surveys 
of opioid users with the goal of being able to design a device to help 
the needs of this population There could be a second visit in which 
participants are ask to give feedback on different device protypes regarding 
how they look and how comfortable they are. Both visits could take place 
on the same day.  
 
Part 2- evaluates a set of pilot prototype designs of devices that 
would be used in future studies to help detect when a person is 
close to a life-threatening overdose.  
Study Duration 
Two years from the date of enrollment. 
Study Center(s) 
Single-center 

 
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Objectives 
The primary objective is to determine the population’s need for a 
wearable device that will treat an opioid overdose. Our goal is to 
obtain descriptive data and functional data on the use of a DOVE 
device prototype. Naloxone will not be administered during the trial. 
The DOVE device prototype is investigational. It has not been approved 
or cleared by the FDA.  
 Examples of data collected are: 
 Study participant will be asked about their opioid use 
and overdose history. 
 Accessibility to Naloxone 
 Study participant will be asked to evaluate potential 
wearable device designs 
 Study participant evaluates which devices would be 
more helpful in terms of detection and comfort 
The secondary objective is to evaluate community availability 
status quo of opioid overdose reversal agents in patient 
population. 
 Evaluate severity and prevalence of opioid 
overdoses within patient population. 
 Assess frequency of opioid overdose. 
 
Number of 
Subjects 
 
Part 1: Enrollment of approximately 100 subjects.  
Part 2: Enrollment of approximately 50 subjects. 
 
Main Inclusion 
and Exclusion 
Criteria 
Inclusion Criteria 
 Males and Females 
 21 years of age or older 
 Have used opioids for more than 3 months or will be 
having surgery where opioids will be administered. 
 Able to provide informed consent 
 Moderate 
to 
severe 
chronic pain 
treated 
(by 
prescription or illicitly) with opioids or recreation use 
Exclusion Criteria 
 Pregnancy  

 
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Investigational 
Product  
 
For Part 1 there could be a second visit in which we ask patient’s feedback 
on different device protypes regarding how they look and how comfortable 
they are. Both visits could take place on the same day. The device will not 
function while you are wearing it. 
 
For Part 2 the DOVE prototype device is a wearable device. 
Subjects will be ask to wear the different prototypes of the device 
during the study visit to assess comfort and design. The device will 
not function while you are wearing it. 
Statistical 
Methodology 
Survey answers will be entered into a RedCap database and 
responses will be aggregated and summarized using descriptive 
statistics. To compare differences survey responses among study 
participant subgroups, we will use t-tests or Wilcoxon rank-sum 
tests (F-tests or Kruskal-Wallis test) for continuous variables and 
Pearson chi square tests or Fishers exact tests for categorical 
variables. Linear and logistic regression will be used to assess for 
differences in the continuous and dichotomous outcomes, 
respectively. All hypothesis tests will be two-sided using a two-
sided alpha of 0.05 as our threshold for statistical significance. 
We will use Stata and/or SAS to analyze the data. 
 
BACKGROUND AND STUDY RATIONALE 
This study will be conducted in full accordance with all applicable University of 
Pennsylvania Research Policies and Procedures and all applicable Federal and State 
laws and regulations including [as applicable include the following regulations as they 
apply 45 CFR 46, 21 CFR Parts 50, 54, 56, and 812 and Good Clinical Practice: 
Consolidated Guidelines approved by the All episodes of noncompliance will be 
documented. 
1 Introduction 
In 2017, 70,237 people died following an accidental overdose in the United States.1 Of 
those, 47,600 (67.8%) died following an opioid overdose, a rate of one death every 11 
minutes.2 Current trends predict that accidental overdose deaths continue rising, perhaps 
on an exponential trajectory.3,4 
 
While opioid overdoses affect almost all communities nationally, both rural and urban, 
Philadelphia is one of the most affected cities. Opioid overdose-related statistics are 
staggering and heartbreaking. Philadelphia County (City of Philadelphia) had the second 
highest rates of drug overdose deaths per county in 20165. Although nationally 68% of 
drug deaths involved opioids, more than 80% of drug deaths in Philadelphia involved 
opioids with an average of more than 3 fatal incidents per day.5,6 In the decade between 
2007 and 2017, 5670 individuals died following an opioid overdose in Philadelphia. Until 
it plateaued in 2017, the number of fatal incidents increased every year.6  

 
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1.1 Background and Relevant Literature  
In many instances, tragic overdose deaths could be avoided.3 Within 5 minutes of an 
opioid overdose, an individual has irreversible brain damage caused by respiratory failure. 
Naloxone is a medication used to block the effects of opioids, especially in overdose. 
Naloxone may be combined with an opioid to decrease the risk of opioid misuse. When 
given intravenously, Naloxone works within two minutes, and when injected into a muscle, 
it works within five minutes; it may also be sprayed into the nose. The effects of Naloxone 
last about half an hour to an hour. Multiple doses may be required. If desired response is 
not obtained, doses should be repeated at 2 to 3 minute intervals. Without intervention, 
preventable deaths continue to occur [ 
Figure 1]. Life-threatening opioid overdose requires someone to assess breathing status 
and if needed, administer Naloxone [Figure 2]. 
 
Figure 1: Overdose Progression with Naloxone Intervention 
 
Figure 2: Overdose Progression without Naloxone Intervention 
 
At the time of opioid overdose, the person overdosing not only needs to have Naloxone 
available, but they need another person to administer the Naloxone, and quickly. Since 
someone is needed to administer, the bystander must also be trained or, at the minimum, 
comfortable administering the drug. While the American Heart Association added 
Naloxone administration as a special situation for the cardiopulmonary resuscitation 
(CPR) training in 2015, the median county training rates are generally low.8,9 In 2020, the 
median county training rate was just 2.39%10. Still, the bystander must be able to access 
the patient. Since 1999, a patient was found alone following fatal overdose in 70,000 
cases.11 While Naloxone is readily available today, many overdose victims are not found 
in time for administration of Naloxone. After five minutes without Naloxone intervention, 
a patient may continue to decompensate, become permanently disabled, or die.1 Despite 
Naloxone being broadly distributed and used as an overdose reversal agent since the 
1970’s, the rate of opioid overdose fatalities has only increased.12  Naloxone is thus a 
                                                 
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solution, but not the solution. For Naloxone to be successful, drug delivery is dependent 
on variables that must be independent of variables that require human action. 
 
While a strategy for the opioid epidemic could rely on increasing Naloxone accessibility, 
designers may also be inclined to reconsider how the medication is deployed. Two major 
strategies are (1) for more individuals to carry Naloxone and (2) for more distribution 
points for Naloxone13–16. In Pennsylvania, Secretary of Health Rachel Levine issued a 
blanket standing order to permit over the counter Naloxone distribution: “this standing 
order may be used by Eligible Persons as a prescription or third-party prescription to 
obtain Naloxone from a pharmacy in the event that they are unable to obtain Naloxone or 
a prescription for Naloxone from their regular health care providers or another source.”17 
 
1.2 Name and Description of the Investigational Product  
Device name: DOVE Prototype 
Device Description: The device is a de novo device called the DOVE (Delivery of Opioid 
agonists for Ventilatory Emergencies) Device.  During part 2 of the study different 
prototypes of the device design will be evaluated without drug for comfort, fit, design, etc.  
The data collected will be preliminary data for a future study that aims to detect opioid 
overdose and inject Naloxone.  
While the integration of a sensor to recognize opioid overdose and a direct reversal-agent 
response in a device is novel, predicate devices sense physiological variables and 
administer a drug in response to a change in the physiological variable. For example, the 
FreeO2 wearable device monitors hospitalized COPD patients by assessing SpO2.18 In 
response to SpO2 below the target range, the device adjusts a valve that changes O2 
flow. 18 Likewise, a sweat-based glucose monitor (EOFlow) has been proposed in 
conjunction with transdermal glucose delivery.19  
 
Device category: 
Category B Device 
Intended use: During Part 2 we will evaluate different prototypes of the device.  
At a future time, the final DOVE device would be a wearable device that has components 
that can noninvasively sense overdose and administer commercially available opioid 
antagonist. DOVE would be substantially equivalent to the FreeO2 device in its continual 
assessment of a variable and threshold for response. 
 
      Ankle   
 
     Cannula               Wrist                         Shoulder Deltoid  
 
 
 
       
  

 
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1.2.1 Nonclinical Data 
There is no animal model appropriate for testing the DOVE device, and therefore we have 
not done pre-clinical testing. Like FreeO2’s pulse oximetry, DOVE would analyze 
physiologically associated waveforms and test whether those waveforms elicit a threshold 
that prompts the agent to response.  
2 
Study Objectives 
2.1 
Primary Objective 
The primary objective of Part 1 is to determine the opioid user population’s need for a 
wearable device that will treat an opioid overdose. The primary objective of Part 2 is to 
obtain descriptive data and functional data on DOVE device prototypes. Naloxone will not 
be administered during the trial. Examples of data collected are: 
 Study participant will be asked about their opioid use and overdose history. 
 Accessibility to Naloxone. 
 Study participant will be asked to evaluate potential wearable device designs 
(Part 2 only). 
 Study participant evaluates which devices would be more helpful in terms of 
detection and comfort (Part 2 only). 
2.2     Secondary Objectives  
The secondary object of Part 1 is to evaluate community availability status quo of opioid 
overdose reversal agents in study participant population. 
 
 Evaluate severity and prevalence of opioid overdoses within study 
participant population. 
 
 Assess frequency of opioid overdose. 
3 
Investigational Plan  
3.1 General Design 
The study will be a two-part, pilot study to evaluate feasibility and potential needs of opioid 
users. The study will obtain descriptive data on the use of the DOVE device prototype. 
Study population will consist of study participants who use opioids either after surgical 
procedure or recreationally.  Part 1 will consist of a one-time short questionnaire. Healthy 
volunteers may be enrolled in Part 2 during the device modification phase. Part 2 can 
consist of more than one visit. At no point during in the study will Naloxone be 
administered.  
 

 
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Part 1 will be an exploratory study, during which will administer questionnaires to develop 
a better understanding of factors influencing the needs of the population.  Subjects could 
be given the option of completing part 1 and 2 in the same day.  
 
Part 2 is an exploratory study. Before the start of the device phase, subjects will be 
surveyed for comfort and subjective concerns. They will be shown the device and asked 
their opinion on design and comfort. The device may undergo minor modifications in 
response to functionality and subject comfort, and for iterative improvements such as the 
shape.  We will test the device on participants for comfort, fit and design, using the results 
to improve the device, and then test the device again.  This cycle will be continued until 
we have optimized the prototype device. We will record subject’s verbal feedback, in order 
to guide the process of optimizing the device.  At the end of Part 2, we will have optimized 
the design of the device for comfort and design preference. In part 2 there may be follow-
up testing. Naloxone will not be administered during the study. 
3.1.2 Screening Phase 
Subjects will be recruited directly from clinics associated with the Hospital of the 
University of Pennsylvania, physician referrals, and IRB-approved advertisements 
targeting the Delaware Valley region.  If a potential study participant is considered to be 
eligible, he/she will be referred to the research staff to participate in the initial telephone 
screening. A series of questions will be asked over the phone to confirm eligibility. 
Potential subjects that are eligible based on study criteria will be brought in for the 
baseline visit. Study participant may also be enrolled in clinic. The screening and baseline 
visit may occur on the same day. 
3.1.2 Study Design Phase  
The wearable design phase (WDP) will consist of wearing the DOVE device for part 2. 
During part 1 subjects will not be required to wear the device. They would only be shown 
the device and asked their opinion on design and comfort.  
 
In part 2, before the start of the wearable design phase, subjects will be surveyed for 
comfort and subjective concerns. The device may undergo minor changes in response to 
functionality and subject comfort. Subjects could be given the option of completing part 1 
and 2 in the same day.  
3.1.2 Follow Up Phase 
There is no follow-up period for the study.   
3.2 Study Endpoints  
3.2.1 Primary Study Endpoints 
The primary objectives are descriptive and designed as a feasibility study. Descriptive 
data will be collected on the following:  
 Assessing for subject comfort and tolerability of the DOVE device 

 
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o Documenting subject comfort and subjective participant opinions of device 
wearability  
3.2.2 Secondary Study Endpoints 
Evaluate community availability status quo of opioid overdose reversal agents in study 
participant population. 
 
 Evaluate severity and prevalence of opioid overdoses within study 
participant population. 
 
 Assess frequency of opioid overdose. 
4 
Study Population and Duration of Participation  
4.1 Inclusion Criteria 
 Males and Females 
 21 years of age or older 
 Have used opioids for more than 3 months or will be having surgery where 
opioids will be administered. 
 Able to provide informed consent 
 Moderate to severe chronic pain treated (by prescription or illicitly) with opioids 
or recreation use 
4.2 Exclusion Criteria 
 Pregnant 
4.3 Subject Recruitment  
Subject recruitment will occur through Penn Medicine Faculty engagement, particularly 
referrals from Penn physicians. The study staff will send emails to Penn Medicine 
physicians, asking them to refer subjects to study personnel for contact during recruitment 
and/or seeking permission to contact study participant identified through screening. We 
also plan to use IRB-approved advertisements targeting the Delaware Valley region.  All 
ads will be submitted for IRB approval prior to use.  Subjects may also be recruited from 
PennSeek and Pennomics.  We will seek permission to contact from their physicians to 
approach the patient for recruitment into the study.  If the physician does not respond, the 
study team will send the patient an IRB-approved recruitment letter and follow up with a 
phone call at least one week after.    
4.4 Duration of Study Participation 
Total duration of study participation for enrolled subjects will be approximately 2-3 hours 
per visit for each of the parts. 
4.5 Total Number of Subjects and Sites  
For Part 1 and 2, up to 150 subjects will be enrolled.  

 
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Part 1: Enrollment of approximately 100 subjects.  
Part 2: Enrollment of approximately 50 subjects. 
 
Subjects enrolled in Part 1 will be asked if they are interested in participating in part 2 but 
will need to again go through screening and enrollment. 
4.6 Vulnerable Populations:  
No vulnerable populations will be used in this study. 
5  Study design phase  
5.1 Receipt  
For Part 1, all questionnaires will be administered to the subjects by the clinical research 
team.  
For Part 2, the device will be delivered by the manufacturer to the clinical research team.  
The clinical research team will maintain records logs regarding device dispensing and 
return devices. This will be in addition to any records kept by the sponsor. The sponsor 
will maintain the device disposal logs.   
5.2 Storage 
The devices and supplies will be stored in a locked room where only study personnel will 
have access. 
5.3 Blinding 
There is no blinding to the study. 
5.4 Administration and Accountability    
For Part 2, the prototype of the device study will be given to each subject at the study 
visit. A product log will be kept in which product reconciliation will be collected at every 
visit with information on product dispensing, such as: date dispensed, and to which 
subjects the device was given and returned. A standard form will be utilized to document 
this information throughout the study period.  
5.5 Subject Compliance Monitoring 
For Part 2 subject are only required to wear the device for the duration of the visit.  
5.5.1 Return or Destruction of Investigational Product 
The investigational product will be returned to the investigator for continued development 
at the conclusion of the study visit. Date of return will be logged on the initial reconciliation 
case report form (CRF). A standard form will be utilized to document the return and 
destruction of the prototype devices.  
 
6 Study Procedures 
Table 1: Schedule of Study Procedures  

 
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Study Procedures 
Part 1 
Part 2 
Screening 
Baseline 
Screening 
Baseline 
Number of visits 
1 
1 
1 
1-2 
Review 
Inclusion/Exclusion Criteria 
X 
 
X 
 
Informed Consent 
X 
 
X 
 
Demographics/Medical 
History 
X 
 
X 
 
Questionnaire 
 
X 
 
X 
Prior/Concomitant 
Medications 
X 
X 
X 
X 
Dispense Investigational 
Product 
 
 
 
X 
Collect Investigational 
Product 
 
 
 
X 
 
Assessment of possible 
AE 
 
 
 
X 
 
6.1.1 Screening (Parts 1 and 2) 
 Review of Inclusion/Exclusion criteria 
6.1.2 Baseline Visit  
 Signed informed consent 
 Review of demographics, medical history and medications  
 Questionnaire 
 Dispense Investigational Product (only Part 2) 
 Collect Investigational Product (only Part 2) 
  Assessment of possible Adverse Events (only Part 2) 
6.2 Follow Up Phase of the Study 
There will be no additional follow-up visit after completion of the study.  
6.3 Subject Withdrawal 
Early withdrawal from the protocol poses no safety risk to participating subjects.  The 
study participant may choose to withdraw at any point while participating in the protocol 
without impact to their care.  They may also be discontinued from the study at the 
discretion of the Investigator for lack of adherence to the protocol, safety concerns, or 
study termination.   
6.4 Data Collection and Follow-up for Withdrawn Subjects 
There is no need for follow-up for subjects who complete or withdraw from the study.  

 
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7 Study Evaluations and Measurements  
7.1 Medical Record Review 
 Date of birth & Demographics 
 Medications 
 Medical/surgical history  
 Information related to opioid use and history of overdose 
 EPIC chart review to ensure subject meets inclusion criteria or does not meet 
exclusion criteria.  
7.2 Pregnancy Testing 
There will not be any pregnancy test. Study participant will be asked if they are pregnant 
or not. 
 
7.3 Laboratory Evaluations 
There will not be any laboratory evaluations. 
 
7.4 Other Evaluations, Measures 
Part 1-  Questionnaire will be given to subjects once they have been consented.  
 
Part 2 - Participants will also be surveyed/interviewed for their subjective experience with 
the DOVE prototype device. The interview and questionnaire will ensure that key topics 
are covered, while also allowing the subject to discuss issues and experiences with the 
prototype device that the investigational team has not considered.  
 
7.5  Safety Evaluations 
The principal investigator will be responsible for evaluating and maintaining the highest 
safety standards and practices. For the purposes of this trial, there will not be a DSMB. 
Any adverse device events will be reported to the principal investigator and sponsor.  
8 Statistical Plan 
Survey answers will be entered into a RedCap database and responses will be 
aggregated and summarized using descriptive statistics. To compare differences survey 
responses among study participant subgroups, we will use t-tests or Wilcoxon rank-sum 
tests (F-tests or Kruskal-Wallis test) for continuous variables and Pearson chi square 
tests or Fishers exact tests for categorical variables. Linear and logistic regression will be 
used to assess for differences in the continuous and dichotomous outcomes, respectively. 
All hypothesis tests will be two-sided using a two-sided alpha of 0.05 as our threshold for 
statistical significance. We will use Stata and/or SAS to analyze the data. 

 
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8.1 Primary Endpoint 
For part 1 and 2 the primary objective is qualitative, only descriptive information will be 
obtained. The endpoint will be collection of feasibility and safety data. 
 
As the primary objectives are descriptive and designed as a feasibility study, no power 
analysis will be performed. The sample size is one of convenience and limited by 
resources. 
8.2 Secondary Endpoints  
Evaluate community availability status quo of opioid overdose reversal agents in study 
participant population. 
 
 Evaluate severity and prevalence of opioid overdoses within study 
participant population. 
 
 Assess frequency of opioid overdose. 
 
 Assess frequency of opioid overdose. 
8.3 Sample Size and Power Determination 
As the primary objectives are descriptive and designed as a feasibility study, no power 
analysis will be performed. The sample size is one of convenience and limited by 
resources. 
8.4 Statistical Methods 
For the primary objective, qualitative data will be analyzed with descriptive charts and 
discussion.   The secondary objective and other continuous variables will be analyzed by 
descriptive and inferential statistics.  
 
Survey answers will be entered into a RedCap database and responses will be 
aggregated and summarized using descriptive statistics. To compare differences survey 
responses among study participant subgroups, we will use t-tests or Wilcoxon rank-sum 
tests (F-tests or Kruskal-Wallis test) for continuous variables and Pearson chi square 
tests or Fishers exact tests for categorical variables. Linear and logistic regression will be 
used to assess for differences in the continuous and dichotomous outcomes, respectively. 
All hypothesis tests will be two-sided using a two-sided alpha of 0.05 as our threshold for 
statistical significance. We will use Stata and/or SAS to analyze the data. 
8.4.1 Baseline Data 
Baseline and demographic characteristics will be summarized by standard descriptive 
statistics (including mean and standard deviation for continuous variables such as age 
and standard percentages for categorical variables such as gender). 
8.5 Subject Population(s) for Analysis 
Any subjects enrolled in the study will be included in the data.  

 
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9. Safety and Adverse Events 
9.1 Definitions 
9.1.1 Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or 
worsens in severity during the course of the study.  Intercurrent illnesses or injuries should 
be regarded as adverse events.  Abnormal results of diagnostic procedures are 
considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
For FDA regulated studies, the FDA defines an adverse event as the following:  
 
Adverse event means any untoward medical occurrence associated with the use of a drug 
in humans whether or not considered drug related.  
9.1.2 Serious Adverse Event 
Adverse events are classified as serious or non-serious.  
A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are 
clearly of major clinical significance. They may jeopardize the subject, and may require 
intervention to prevent one of the other serious outcomes noted above.  For example, 
drug overdose or abuse, a seizure that did not result in in-patient hospitalization, or 
intensive treatment of bronchospasm in an emergency department would typically be 
considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as 
non-serious adverse events.  
9.2 Recording of Adverse Events 
Any AE/ADE will be recorded by the Clinical Research Coordinator on the AE CRF, and 
signed off by the PI. Recording of adverse events will begin when the first subject is 
enrolled and will end when the last subject has completed all study procedures. 
Unanticipated adverse events (serious and non-serious) will be reported to the Penn IRB, 
in accordance with federal and institutional requirements.  

 
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At each contact with the subject, the investigator will seek information on adverse events 
by specific questioning and, as appropriate, by examination.  Upon removal of the device, 
research personal will evaluate for lesion at site of placement on subject via inspection 
and palpation. Information on all adverse events will be recorded immediately in the 
adverse event case report form (CRF).   
 
All adverse events occurring during the study period (from study intervention start to end 
of the study) will be recorded by research personnel.  The clinical course of each event 
will be followed until resolution, stabilization, or until it has been determined that the study 
intervention or participation is not the cause.  Serious adverse events that are still ongoing 
at the end of the study period will be followed up to determine the final outcome.  Any 
serious adverse event that occurs after the study period and is considered to be possibly 
related to the study intervention or study participation will be recorded and reported 
immediately. 
9.3 Relationship of AE to Study  
All adverse events and adverse device effects will be reported according to the timeline 
below:  
 
Serious Adverse Event 
Within 24 hours 
 
The PI shall immediately evaluate and assess each adverse events, serious adverse 
event and 
adverse device effects. 
9.4 Reporting of Adverse Events, Adverse Device Effects and Unanticipated 
Problems 
Investigators must conform to the adverse event reporting timelines, formats and 
requirements of the various entities to which they are responsible.  
 
The minimum necessary information to be provided at the time of the initial report 
includes: 
 Study identifier 
 Study Center 
 Subject number 
 A description of the event 
 Date of onset 
 Current status 
 Whether study intervention was discontinued 
 The reason why the event is classified as 
serious 
 Investigator assessment of the association 
between the event and study intervention 
 
Additionally, all other events (unanticipated problems, adverse reactions, unanticipated 
adverse device effects and subject complaints will be recorded and reported with respect 
to institutional and federal policies. 
  

 
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9.5  Follow-up reports 
9.5.1 Unresolved SAEs 
 
If an SAE has not resolved at the time of the initial report and new information arises that 
changes the investigator’s assessment of the event, a follow-up report including all 
relevant new or reassessed information (e.g., concomitant medication, medical history) 
should be submitted to the IRB. The investigator is responsible for ensuring that all SAE 
are followed until either resolved or stable.  
9.5.2 Adverse Device Effects  
After reporting an ADE to the Sponsor, within the following 48 hours, the investigator 
shall provide further information, as applicable, on the device effect in the form of a 
written narrative. This should include any other diagnostic information that will assist 
the understanding of the event. Significant new information on ongoing unanticipated 
adverse device effects shall be provided promptly to the study sponsor.  
9.5.3 Protocol Exceptions and Deviations  
Protocol exceptions from the protocol must receive PI approval before they are 
initiated. Any protocol deviations initiated without PI approval that may affect the 
scientific soundness of the study, or affect the rights, safety, or welfare of study 
subjects, must be reported to the PI as soon as a possible, but no later than 5 
working days of the protocol deviation.  
9.6 Investigator reporting: notifying the Sponsor 
9.6.1 Adverse Events, Serious Adverse Events, & Adverse Device Effects 
Any event that occurs any time during or after the research study, which in the opinion of 
the principal investigator is related and unexpected (see definitions under unanticipated 
problem) will be reported to the Penn IRB within 10 working days. Any event that is related 
and unexpected (see definitions under unanticipated problem) AND is fatal or life 
threatening will be reported to the IRB within 3 working days.   
After reporting an ADE to the Sponsor, within the following 48 hours, the investigator shall 
provide further information, as applicable, on the device effect in the form of a written 
narrative. This should include any other diagnostic information that will assist the 
understanding of the event. Significant new information on ongoing unanticipated adverse 
device effects shall be provided promptly to the study sponsor 
9.7 Protocol Exceptions and Deviations  
Protocol exceptions must receive IRB approval before they are initiated. Any protocol 
deviations initiated without IRB approval that may affect the scientific soundness of 
the study, or affect the rights, safety, or welfare of study subjects, must be reported to 
the IRB as soon as a possible, but no later than 5 working days of the protocol 
deviation.  

 
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9.8 Other Events 
Certain events are required to be reported to the IRB in an expedited fashion as per 
21 CFR 812.150:  
 Device Recall, Repair, or Disposal: If the device manufacturer requests a recall, 
repair, or disposal of the DOVE device, the IRB will be notified within 30 days of 
the request device recall. 
 Failure to Obtain Consent: If an investigator fails to obtain informed consent, the 
IRB must be notified within 5 working days. 
 Final Report: A final report on the study will be submitted to IRB within 6 months 
of study completion. 
Additionally all other events (see list below) will be recorded and reported with respect 
to institutional and federal policies as described in the Penn Manual. All events as 
defined above will be reported to the Penn IRB by study personnel within the 
required timeline per the IRB Reportable events policy.  
 Any adverse event that would cause the sponsor to modify the protocol or informed 
consent form, or would prompt other action by the IRB to assure protection of 
human subjects.  
 Information that indicates a change to the risks or potential benefits of the 
research, in terms of severity or frequency. For example:  
 An interim analysis indicates that participants have a lower rate of response to 
treatment than initially expected.  
 Safety monitoring indicates that a particular side effect is more severe, or more 
frequent than initially expected.  
 A paper is published from another study that shows that an arm of your research 
study is of no therapeutic value.  
 Breach of confidentiality  
 Change to the protocol taken without prior IRB review to eliminate apparent 
immediate hazard to a research participant.  
 Incarceration of a participant when the research was not previously approved 
under Subpart C and the investigator believes it is in the best interest of the subject 
to remain on the study.  
 Complaint of a participant when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team.  
10 Reporting Process  
Report unanticipated problems as defined above to the Penn IRB using the form: 
“Unanticipated Problems Posing Risks to Subjects or Others Including Reportable 
Adverse Events” or as a written report of the event (including a description of the event 
with information regarding its fulfillment of the above criteria, follow-up/resolution and 
need for revision to consent form and/or other study documentation).  
Copies of each report and documentation of IRB notification and receipt will be kept 
in the Clinical Investigator’s study file.  

 
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10.1 Devices  
10.1.1 Additional reporting requirements 
Sponsors are also required to identify in IND/IDE safety reports all previous reports 
concerning similar adverse events and to analyze the significance of the current event in 
light of the previous reports. 
10.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents.  Examples of these original documents, 
and data records include: hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at 
the laboratories, and at medico-technical departments involved in the clinical trial. 
 10.3 Case Report Forms (CRFs) 
The study case report form (CRF) is the primary data collection instrument for the study.  
All data requested on the CRF must be recorded.  All missing data must be explained.  If 
a space on the CRF is left blank because the procedure was not done or the question 
was not asked, write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  
All entries should be printed legibly in black ink.  If any entry error has been made, to 
correct such an error, draw a single straight line through the incorrect entry and enter the 
correct data above it.  All such changes must be initialed and dated.  DO NOT ERASE 
OR WHITE OUT ERRORS.  For clarification of illegible or uncertain entries, print the 
clarification above the item, then initial and date it.  
 
11 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the 
following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.   
 
Full privacy will be expected to each participant in the study. To identify potential subjects 
in the study, research personnel responsible for consenting and enrollment will identify 
potential subjects via active lists of patients and referrals from clinical faculty. Research 

 
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personnel will then read through electronic records to briefly review eligibility criteria. If 
the potential participant meets eligibility criteria, research personnel will then approach 
the subject if they are available in clinic, or call them. 
 
If enrolled in clinic: The potential subject will be alone in the room without risk of having 
patient’s privacy compromised during enrollment/consent. If there are family members or 
friends around a potential subject at time of enrollment/consent, potential subjects will be 
asked if they are comfortable discussing the study in the setting of other individuals.  
 
If enrolled via telephone encounter: The study participant will first be asked if he is 
interested in talking to research personnel about possible enrollment. They will have the 
opportunity to ask us to call back another time. 
 
All research personnel will follow privacy guidelines as described in CITI training 
biomedical and good behavior research modules, as required by all Penn study 
participants. 
12 Data Collection and Management  
Any person that meets screening criteria will be included in the data collection and 
analysis throughout and at the completion of the study. All clinical trial team members will 
receive training in responsible conduct of research using the Penn IRB standard training 
requirements. This will include data management and procedures for maintaining 
confidentiality and subject safety. The study team and sponsor will meet periodically to 
review the progress of the study, paying particular attention to any missing data – to 
ensure that all forms are completed on schedule and all data is entered, verified and 
available for analysis. Data will be stored in password protected files, on a secure 
research server with data backup preformed nightly. Protected health information linking 
the assigned unique identifier to the subject identity will only be kept as an electronic 
document and will be held on the shared Penn Medicine e-drive. This document will be 
password protected and only study personnel will have access. Study files will be kept in 
a locked filing cabinet. Data will be maintained in locked files to which only authorized 
study personnel will have access. Data collected will be entered in RedCap, excel and/or 
CTMS. 
13 Records Retention  
It is the investigator’s responsibility to retain study essential documents for at least 2 years 
after the last approval of a marketing application in their country and until there are no 
pending or contemplated marketing applications in their country or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product. These documents should be retained for a longer period if required by an 
agreement with the sponsor. In such an instance, it is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be 
retained.  

 
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14 Study Monitoring, Auditing, and Inspecting 
The primary investigator will be responsible for monitoring all information. The investigator 
will allocate adequate time for such monitoring activities.   
The investigator will permit study-related monitoring, audits, and inspections by the 
EC/IRB and University compliance and quality assurance groups of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, 
study data etc.).  The investigator will ensure the capability for inspections of applicable 
study-related facilities. 
 15 Ethical Considerations 
This study is to be conducted in accordance with applicable US government regulations 
and international standards of Good Clinical Practice, and applicable institutional 
research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted 
independent Ethics Committee (EC) or Institutional Review Board (IRB), in agreement 
with local legal prescriptions, for formal approval of the study conduct.  The decision of 
the IRB concerning the conduct of the study will be made in writing to the investigator and 
a copy of this decision will be provided to the sponsor before commencement of this study.  
16 Risks 
Potential study risks include the accidental breach of confidential patient health 
information related to the collection of survey and EMR data. Precautions will be taken to 
ensure that strict confidentiality is maintained. This risk has been mitigated by extensive 
privacy protection protocols, a highly secure data storage system at Penn Medicine, and 
a plan to remove identifiers from the data wherever possible. In addition, all study 
personnel will be held to high standards of upholding confidentiality and safeguarding 
patient privacy. To ensure that patient confidentiality is preserved, individual identifiers 
(such as name) are stored in a single password protected system that is accessible to the 
principle investigator and research team. This system is hosted on site at Penn Medicine 
and is protected by a secure firewall. Any datasets and computer files that leave the 
firewall will be stripped of all identifiers besides the study ID. The study ID will also be 
used on all analytical files. Confidentiality of all study data will be maintained by restricting 
access to the identifiable information only to approved study staff who have received 
subject confidentiality and privacy training. 
 17 Benefits 
For Part 1 and 2 there are no direct expected benefits to the healthy participants for 
participating in this study.  
Long-term, the technology aims to improve the quality of life for patients who suffer from 
opioid abuse. 

 
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17.1  Risk Benefit Assessment 
It is the investigators’ belief that the benefits to society outweigh the minimal risks with 
the device. 
17.2  Informed Consent Process / HIPAA Authorization  
All study subjects who meeting enrollment criteria will be required to provide personal 
consent. Primarily, the research coordinator will obtain consent, but other IRB approved 
study personnel will be permitted to obtain consent.  
 
Consent will be obtained, when possible, via in person paper consent. Once the form is 
completed and signed by the individual giving consent, all consent forms will be placed 
with other securely stored documents. 
During the consent process, the consent form will be reviewed, as well as the description 
of the questionnaire, device and study procedures, the purpose of the study, the risks and 
benefits, and the voluntary nature of research participation. 
  
To prevent coercion and ensure all information is understood, subjects will have the 
opportunity to ask as many questions as they need and will have the option to withdrawal 
from the study. 
18 Study Finances 
18.1 Funding Source 
 
 
The study will be financed through Funded by a Penn-internal grant from Penn's Medical Device 
Accelerator (MDA) 
18.2 Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania 
Policy on Conflicts of Interest Related to Research.  
 
19 Publication Plan 
The PI and the research team will have complete access to the data collected. 
 
Part 1 is currently designed for exploratory work but publication could come from it. This 
part is intended for baseline data on device design and population needs. 
Part 2 may lead to publication. This part is intended for baseline data on the device. 
 20 References 
. Hedegaard, H., Warner, M. & Miniño, A. M. Drug Overdose Deaths in the United States, 
1999-2016. NCHS Data Brief 1–8 (2017). doi:10.1016/j.neulet.2010.07.040 
2. Centers for Disease Control and Prevention. Data Brief 329: Drug Overdose Deaths in 

 
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Page 21 
the United States. (2017). 
3. Rudd, R., Aleshire, N., Zibbel, J. E. & Gladden, M. R. Increases in Drug and Opioid 
Overdose Deaths — United States , 2000 – 2014. Am. J. Transplant. 64, 1378–1382 
(2016). 
4. Burke, D. S. et al. Changing dynamics of the drug overdose epidemic in the United 
States from 1979 through 2016. Science (80-. ). 361, eaau1184 (2018). 
5. Eichel, L. & Pharis, M. Philadelphia’s Drug Overdose Death Rate Among Highest in 
Nation. (2018). 
6. Whelan, A. The opioid overdose crisis is hitting all of Philadelphia, new data show. The 
Philadelphia Inquirer (2018). 
7. Whelan, A. The opioid overdose crisis is hitting all of Philadelphia, new data show. The 
Philadelphia Inquirer (2018). 
8. Lavonas, E. J. et al. Part 10: Special Circumstances of Resuscitation. Circulation 132, 
S501–S518 (2015). 
9. Anderson, M. L. et al. Rates of Cardiopulmonary Resuscitation Training in the United 
States. JAMA Intern. Med. 174, 194 (2014). 
10. Anderson, M. L. et al. Rates of Cardiopulmonary Resuscitation Training in the United 
States. JAMA Intern. Med. 174, 194 (2014). 
11. Centers for Disease Control and Prevention. CDC Press Release (2018 - Dec 21). 
(2018). 
12. Heavey, S. C. et al. ‘I have it just in case’ — Naloxone access and changes in opioid 
use behaviours. Int. J. Drug Policy 51, 27–35 (2018). 
13. Kerensky, T. & Walley, A. Y. Opioid overdose prevention and naloxone rescue kits: 
what we know and what we don’t know. Addict. Sci. Clin. Pract. 12, 4 (2017). 
14. Strang, J. & McDonald, R. Preventing opioid overdose deaths with take-home 
naloxone. EMCDDA Insights 20, (2016). 
15. Strang, J., Bird, S. M., Dietze, P., Gerra, G. & McLellan, A. T. Take-home emergency 
naloxone to prevent deaths from heroin overdose. BMJ 349, g6580–g6580 (2014). 
16. Darke, S. & Hall, W. The distribution of naloxone to heroin users. Addiction 92, 1195–
1200 (1997). 
17. Levine, R. L. STANDING ORDER DOH-002-2018 Naloxone Prescription for 
Overdose Prevention. (2018). 
18. Lellouche, F. et al. Automated oxygen titration and weaning with FreeO2 in patients 
with acute exacerbation of COPD: a pilot randomized trial. Int. J. Chron. Obstruct. 
Pulmon. Dis. Volume 11, 1983–1990 (2016). 
19. Lee, H. et al. Wearable/disposable sweat-based glucose monitoring device with 
multistage transdermal drug delivery module. Sci. Adv. 3, e1601314 (2017). 
20. Rzasa Lynn, R. & Galinkin, J. Naloxone dosage for opioid reversal: current evidence 
and clinical implications. Ther. Adv. Drug Saf. 9, 63–88 (2018).