A Single Center Study on the Functionality of the Pulse Oximeter and Accelerometer Portions of a Novel Wearable Device
Phase: NA
Conditions: Hypoxic Events
Sponsor: University of Pennsylvania

​A​ ​SINGLE​ ​CENTER​ ​STUDY​ ​ON​ ​THE​ ​FUNCTIONALITY​ ​OF​ ​THE​ ​PULSE​
​OXIMETER​ ​AND​ ​ACCELEROMETER​ ​PORTIONS​ ​OF​ ​A​ ​NOVEL​ ​WEARABLE​
​DEVICE​
​Principal Investigator​
​Jacob Brenner, MD, PhD​
​Pulmonary, Allergy & Critical Care Division​
​844 West Gates​
​3600 Spruce Street Philadelphia PA 19104​
​(650) 799-7024​
​Jacob.Brenner@pennmedicine.upenn.edu​
​Regulatory Sponsor​
​Jacob Brenner, MD, PhD​
​Pulmonary, Allergy & Critical Care Division​
​844 West Gates​
​3600 Spruce Street Philadelphia PA 19104​
​(650) 799-7024​
​Jacob.Brenner@pennmedicine.upenn.edu​
​NIH Grant Number​
​N/A (Funded by Coulter Translational Research Grant)​
​Investigational Product:​
​DOVE Device Prototype​
​IRB Number:​
849910​
​ClinicalTrials.gov Number​
​NCT05197790​

​DOVE Prototype​​Trial​
​Version 1.2                                                     March 21, 2022​
​Table of Contents​
​Contents​
​L​​IST​​OF​​A​​BBREVIATIONS​
​4​
​S​​TUDY​​S​​UMMARY​
​5​
​I​​NCLUSION​​C​​RITERIA​
​5​
​E​​XCLUSION​​C​​RITERIA​
​5​
​1 I​​NTRODUCTION​
​6​
​1.1 B​​ACKGROUND​​AND​​R​​ELEVANT​​L​​ITERATURE​
​6​
​1.2 N​​AME​​AND​​D​​ESCRIPTION​​OF​​THE​​I​​NVESTIGATIONAL​​P​​RODUCT​
​7​
​D​​EVICE​​NAME​: DOVE P​​ROTOTYPE​
​7​
​1.2.1​
​Nonclinical Data​
​8​
​2​
​S​​TUDY​​O​​BJECTIVES​
​8​
​2.1 P​​RIMARY​​O​​BJECTIVE​
​8​
​2.2 S​​ECONDARY​​O​​BJECTIVES​
​8​
​3​
​I​​NVESTIGATIONAL​​P​​LAN​
​8​
​3.1​
​G​​ENERAL​​D​​ESIGN​
​8​
​3.1.1 Follow Up Phase​
​9​
​3.2 S​​TUDY​​E​​NDPOINTS​
​9​
​3.2.1 Primary Study Endpoints​
​9​
​3.2.2 Secondary Study Endpoints​
​9​
​4. S​​TUDY​​P​​OPULATION​​AND​​D​​URATION​​OF​​P​​ARTICIPATION​
​9​
​4.1​
​I​​NCLUSION​​C​​RITERIA​
​9​
​4.3​
​S​​UBJECT​​R​​ECRUITMENT​
​10​
​4.4​
​D​​URATION​​OF​​S​​TUDY​​P​​ARTICIPATION​
​10​
​4.5​
​T​​OTAL​​N​​UMBER​​OF​​S​​UBJECTS​​AND​​S​​ITES​
​10​
​4.6​
​V​​ULNERABLE​​P​​OPULATIONS​:​
​10​
​5​
​S​​TUDY​​DESIGN​​PHASE​
​10​
​5.1​
​R​​ECEIPT​
​10​
​5.2​
​S​​TORAGE​
​11​
​5.3​
​B​​LINDING​
​11​
​5.4​
​A​​DMINISTRATION​​AND​​A​​CCOUNTABILITY​
​11​
​5.5​
​S​​UBJECT​​C​​OMPLIANCE​​M​​ONITORING​
​11​
​5.5.1​
​Return or Destruction of Investigational Product​
​11​
​6​
​S​​TUDY​​P​​ROCEDURES​
​11​
​6.1 S​​CREENING​​AND​​B​​ASELINE​​D​​ATA​​C​​OLLECTION​
​12​
​6.1.1 Device Collection​
​12​
​6.2 F​​OLLOW​​U​​P​​P​​HASE​​OF​​THE​​S​​TUDY​
​12​
​6.3 S​​UBJECT​​W​​ITHDRAWAL​
​12​
​6.4 D​​ATA​​C​​OLLECTION​​AND​​F​​OLLOW​-​​UP​​FOR​​W​​ITHDRAWN​​S​​UBJECTS​
​12​
​7​
​S​​TUDY​​E​​VALUATIONS​​AND​​M​​EASUREMENTS​
​12​
​7.1 M​​EDICAL​​R​​ECORD​​R​​EVIEW​
​12​
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​DOVE Prototype​​Trial​
​Version 1.2                                                     March 21, 2022​
​7.2 P​​REGNANCY​​T​​ESTING​
​12​
​7.3 L​​ABORATORY​​E​​VALUATIONS​
​12​
​7.4 O​​THER​​E​​VALUATIONS​, M​​EASURES​
​13​
​7.5 S​​AFETY​​E​​VALUATIONS​
​13​
​8​
​S​​TATISTICAL​​P​​LAN​
​13​
​8.1​
​P​​RIMARY​​E​​NDPOINT​
​13​
​8.2​
​S​​ECONDARY​​E​​NDPOINTS​
​13​
​8.3​
​S​​AMPLE​​S​​IZE​​AND​​P​​OWER​​D​​ETERMINATION​
​14​
​8.4​
​S​​TATISTICAL​​M​​ETHODS​
​14​
​8.4.1​
​Baseline Data​
​14​
​8.5​
​S​​UBJECT​​P​​OPULATION​(​​S​)​​FOR​​A​​NALYSIS​
​14​
​9. S​​AFETY​​AND​​A​​DVERSE​​E​​VENTS​
​14​
​9.1 D​​EFINITIONS​
​14​
​9.1.1 Adverse Event​
​14​
​9.2 S​​ERIOUS​​A​​DVERSE​​E​​VENT​
​15​
​9.2.1 Recording of Adverse Events​
​15​
​9.3 R​​ELATIONSHIP​​OF​​AE​​TO​​S​​TUDY​
​15​
​9.4 R​​EPORTING​​OF​​A​​DVERSE​​E​​VENTS​, A​​DVERSE​​D​​EVICE​​E​​FFECTS​​AND​​U​​NANTICIPATED​​P​​ROBLEMS​
​16​
​9.5 F​​OLLOW​-​​UP​​REPORTS​
​16​
​9.5.1 Unresolved SAEs​
​16​
​9.5.2 Adverse Device Effects​
​16​
​9.5.3 Protocol Exceptions and Deviations​
​16​
​9.6 I​​NVESTIGATOR​​REPORTING​:​​NOTIFYING​​THE​​S​​PONSOR​
​17​
​9.6.1 Adverse Events, Serious Adverse Events, & Adverse Device Effects​
​17​
​9.7 P​​ROTOCOL​​E​​XCEPTIONS​​AND​​D​​EVIATIONS​
​17​
​9.8 O​​THER​​E​​VENTS​
​17​
​10 R​​EPORTING​​P​​ROCESS​
​18​
​10.1 D​​EVICES​
​18​
​10.1.1 Additional reporting requirements​
​18​
​10.2 S​​OURCE​​D​​OCUMENTS​
​18​
​10.3 C​​ASE​​R​​EPORT​​F​​ORMS​​(CRF​​S​)​
​18​
​11 C​​ONFIDENTIALITY​
​19​
​12 D​​ATA​​C​​OLLECTION​​AND​​M​​ANAGEMENT​
​19​
​13 R​​ECORDS​​R​​ETENTION​
​20​
​14 S​​TUDY​​M​​ONITORING​, A​​UDITING​,​​AND​​I​​NSPECTING​
​20​
​15 E​​THICAL​​C​​ONSIDERATIONS​
​20​
​16 R​​ISKS​
​20​
​17 B​​ENEFITS​
​21​
​17.1 R​​ISK​​B​​ENEFIT​​A​​SSESSMENT​
​21​
​17.2 I​​NFORMED​​C​​ONSENT​​P​​ROCESS​​/ HIPAA A​​UTHORIZATION​
​21​
​18 S​​TUDY​​F​​INANCES​
​21​
​18.1 F​​UNDING​​S​​OURCE​
​21​
​18.2 C​​ONFLICT​​OF​​I​​NTEREST​
​21​
​19 P​​UBLICATION​​P​​LAN​
​21​
​20 R​​EFERENCES​
​22​
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​DOVE Prototype​​Trial​
​Version 1.2                                                     March 21, 2022​
​List of Abbreviations​
​ADE:​​Adverse Device Effect​
​AE:​​Adverse event​
​COPD:​​Chronic Obstructive Pulmonary Disease​
​CRF:​​Case report form​
​DOVE:​​D​elivery of​​O​pioid agonists for​​V​entilatory​​E​mergencies​
​DSMB:​​Data Safety and Monitoring Board​
​SAE:​​Serious Adverse Event​
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​Study Summary​
​Title​
​A​​Single​​Center​​Study​​on​​the​​Functionality​​of​​the​​Pulse​​Oximeter​​and​
​Accelerometer Portions of a Novel Wearable Device​
​Short Title​
​DOVE Device Prototype​
​IRB Number​
​Not yet applicable.​
​Phase​
​Pilot Study​
​Methodology​
​This​ ​study​ ​will​ ​assess​ ​the​ ​reasonable​ ​functionality​ ​of​ ​the​ ​pulse​
​oximetry​​and​​accelerometry​​portions​​of​​a​​prototype​​form​​of​​the​​DOVE​
​medical​​device.​​The​​DOVE​​device​​will​​be​​designed​​with​​the​​intention​
​to​ ​sense​ ​and​ ​respond​ ​to​ ​opioid​ ​overdose.​ ​Study​ ​participants​ ​will​​be​
​asked​​to​​wear​​the​​DOVE​​prototype​​as​​well​​as​​an​​FDA-approved​​pulse​
​oximeter.​ ​The​ ​primary​ ​objective​ ​is​ ​to​ ​assess​​reasonable​​detection​​of​
​hypoxic​ ​episodes.​ ​Participant​ ​movement​ ​will​ ​be​ ​collected​ ​via​ ​the​
​DOVE​ ​accelerometer​ ​on​ ​the​ ​night​ ​of​ ​their​ ​sleep​ ​study.​ ​Relevant​
​variables including skin tone and comfort will be collected.​
​Study Duration​
​2 year​
​Study Center(s)​
​Single-center​
​Objectives​
​The​ ​primary​ ​objective​ ​is​ ​to​ ​assess​ ​the​ ​functionality​ ​of​ ​the​ ​sensor​
​portions​ ​of​​a​​DOVE​​prototype.​​Our​​goal​​is​​to​​obtain​​functional​​data​
​using​ ​a​ ​DOVE​ ​prototype​ ​device​ ​in​ ​patients​ ​who​ ​experience​ ​natural​
​occurring hypoxic events.​
​The​ ​secondary​ ​objective​ ​is​ ​to​ ​evaluate​ ​the​ ​effects​ ​of​ ​patient-level​
​factors​ ​on​ ​data​ ​quality​ ​of​ ​a​ ​DOVE​​prototype.​​Our​​goal​​is​​to​​collect​
​variables​ ​known​​to​​affect​​data​​quality​​and​​real-world​​practicality​​for​
​standard market pulse oximetry devices.​
​Number​
​of​
​Subjects​
​20 subjects​
​Main​​Inclusion​​and​
​Exclusion Criteria​
​Inclusion Criteria​
​●​ ​Males and Females​
​●​ ​21 years of age or older​
​●​ ​Suspected to suffer from hypoxic events​
​●​ ​Able to provide informed consent​
​Exclusion Criteria​
​●​ ​Pregnancy​
​Investigational​
​Product​
​The​ ​DOVE​ ​prototype​ ​device​ ​is​ ​a​ ​wearable​ ​device​ ​meant​ ​to​ ​sense​
​physiological​ ​data,​ ​including​ ​SpO​​2​ ​and​ ​accelerometry.​ ​Functional​

​DOVE Prototype​​Trial​
​Version 1.2                                                     March 21, 2022​
​assessment​​of​​the​​physiological​​sensor​​portions​​of​​the​​device​​will​​be​
​carried​ ​out​ ​in​ ​patients​ ​with​ ​clinical​ ​suspicion​ ​for​ ​hypoxic​ ​events.​
​Subject​​skin​​tone​​and​​comfort​​while​​wearing​​the​​device​​will​​also​​be​
​assessed.​ ​One​ ​of​ ​the​ ​main​ ​patient​ ​populations​ ​that​​could​​potentially​
​benefit from this device are opioid users.​
​Statistical​
​Methodology​
​1.​​We​​will​​use​​descriptive​​and​​inferential​​statistics​​to​​describe​​baseline​
​physiology:​​mean​​[SD]​​SpO​​2​ ​and​​motion,​​and​​significant​​respiratory​
​depression​: SpO​​2​​<90% for more than 10 sec.​
​2.​​We​​will​​validate​​our​​characterization​​of​​physiological​​response​​by​
​comparing​ ​pulse​ ​oximetry​ ​data​ ​from​​the​​DOVE​​prototype​​with​​data​
​obtained from a study-provided, FDA-approved pulse oximeter.​
​B​​ACKGROUND​​AND​​S​​TUDY​​R​​ATIONALE​
​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.​​All​
​episodes of noncompliance will be documented.​
​1 Introduction​
​Over​​93,000​​Americans​​died​​of​​a​​drug​​overdose​​in​​2020,​​the​​highest​​in​​U.S.​​history​​and​​a​​29.4%​
​increase​ ​from​ ​the​ ​previous​ ​year.​​1​ ​The​ ​majority​ ​(~75%)​ ​of​ ​these​ ​deaths​ ​involved​ ​an​ ​opioid,​
​including​ ​heroin,​ ​synthetic​ ​analogs​ ​(e.g.​ ​fentanyl),​ ​and​ ​prescription​ ​medications​ ​(e.g.​
​oxycodone).​​2​ ​The​​staggering​​burden​​of​​opioid​​overdose​​deaths​​in​​the​​U.S.​​has​​been​​rising​​rapidly​
​since​​the​​mid​​2010’s,​​but​​has​​reached​​a​​shocking​​trajectory​​during​​the​​COVID-19​​pandemic.​​3,4​
​And​​although​​opioid​​overdose​​affects​​almost​​every​​corner​​of​​the​​U.S.,​​it​​has​​been​​particularly​
​devastating​ ​in​ ​Philadelphia.​ ​Over​ ​1200​ ​Philadelphians​ ​died​ ​of​ ​drug​ ​overdose​ ​in​ ​2020,​ ​with​
​concerning​ ​disparities​ ​in​ ​rates​ ​of​ ​death​ ​among​​communities​​of​​color.​​5​ ​Fentanyl,​​the​​powerful​
​synthetic​​analog​​of​​heroin,​​was​​involved​​in​​over​​80%​​of​​overdose​​deaths​​in​​Philadelphia.​​5,6​​For​
​almost​​two​​decades,​​opioid​​overdose​​has​​been​​a​​driver​​of​​morbidity​​and​​mortality​​in​​the​​U.S.​
​Novel​ ​therapeutic​ ​interventions​ ​are​ ​desperately​ ​needed​ ​to​ ​abate​ ​this​ ​profound​ ​public​ ​health​
​crisis.​
​1.1 Background and Relevant Literature​
​One​​of​​the​​primary​​physiologic​​effects​​of​​opioids​​is​​respiratory​
​depression,​ ​characterized​ ​by​ ​slower​ ​breathing​ ​rate​ ​and​ ​poor​
​exchange​ ​of​ ​oxygen​ ​for​ ​carbon​ ​dioxide.​​7​ ​In​ ​the​ ​setting​ ​of​ ​an​
​opioid​ ​overdose,​ ​respiratory​ ​depression​ ​can​ ​cause​ ​irreversible​
​brain​​damage​​in​​as​​little​​as​​five​​minutes​​and​​can​​be​​fatal​​if​​not​
​reversed.​
​However,​ ​opioid​ ​overdose​ ​is​ ​not​ ​only​ ​tragic​ ​–​ ​it​ ​is​ ​largely​
​preventable.​ ​Naloxone​ ​is​ ​an​ ​opioid​ ​receptor​ ​antagonist​ ​and​
​overdose​ ​antidote.​ ​It​ ​blocks​ ​the​ ​effects​ ​of​ ​opioids​ ​on​ ​their​
​receptors​ ​and​ ​effectively​ ​draws​ ​an​ ​individual​ ​out​ ​of​
​opioid-induced​ ​respiratory​ ​depression.​ ​Naloxone​ ​can​ ​be​
​administered​ ​intranasally,​ ​intravenously,​ ​intramuscularly,​ ​and​
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​DOVE Prototype​​Trial​
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​subcutaneously.​​8​ ​The​ ​most​ ​common​ ​formulation​ ​is​ ​the​ ​nasal​ ​spray,​ ​brand​ ​name​ ​Narcan,​
​administered​ ​in​ ​4​ ​mg​ ​doses.​ ​Its​ ​effects​ ​last​ ​between​ ​30-60​ ​min;​ ​at​ ​higher​ ​doses​ ​of​ ​opioids,​
​multiple​ ​administrations​ ​of​ ​naloxone​ ​may​ ​be​ ​necessary​ ​to​ ​successfully​ ​reverse​ ​an​ ​overdose.​
​Other​ ​than​ ​overdose​ ​reversal,​ ​naloxone​ ​has​ ​no​ ​adverse​ ​effects​ ​or​ ​other​ ​physiological​
​consequences.​
​Broad​​distribution​​of​​naloxone​​has​​been​​a​​cornerstone​​of​​overdose​​prevention​​strategy​​during​​the​
​opioid​ ​overdose​ ​epidemic.​ ​Over​ ​330,000​ ​prescriptions​ ​for​ ​naloxone​ ​were​ ​filled​ ​in​​2017,​​and​
​wider​​availability​​of​​naloxone​​has​​been​​correlated​​with​​decreased​​overdose​​mortality.​​9​​However,​
​despite​​effective​​distribution​​of​​the​​nasal​​spray,​​overdose​​prevention​​efforts​​remain​​hindered​​by​
​the​​current​​routes​​of​​administration.​​Currently,​​naloxone​​must​​be​​administered​​by​​a​​third-party​
​bystander​​who​​is​​not​​only​​equipped​​with​​the​​overdose​​antidote,​​but​​also​​trained,​​willing,​​and​​able​
​to​ ​use​ ​it.​​Unfortunately,​​52%​​of​​overdose​​deaths​​occur​​in​​a​​setting​​where​​the​​individual​​used​
​alone,​ ​with​ ​no​ ​possibility​ ​for​ ​bystander​ ​intervention.​​10​ ​Particularly​ ​in​ ​the​ ​context​ ​of​ ​the​
​COVID-19​ ​pandemic,​ ​it​ ​is​ ​critical​ ​to​ ​expand​ ​overdose​ ​prevention​ ​strategies​ ​among​ ​the​
​vulnerable proportion of people who use opioids alone.​
​In​​the​​context​​of​​this​​pressing​​clinical​​need,​​our​​team​​is​​developing​​the​​DOVE​​device,​​a​​wearable​
​sensor​ ​that​ ​detects​ ​physiological​ ​signs​ ​of​ ​opioid​ ​overdose​ ​and​ ​automatically​ ​administers​
​naloxone.​ ​To​ ​date,​ ​we​ ​have​ ​developed​ ​a​ ​sensor​ ​system​ ​that​ ​combines​ ​a​ ​pulse​ ​oximeter​ ​and​
​accelerometer​ ​to​ ​detect​ ​signs​ ​of​ ​respiratory​ ​depression​ ​(via​ ​decreased​ ​blood​ ​oxygen)​ ​and​
​decreased​​motor​​activity.​​Our​​next​​objective​​is​​to​​validate​​our​​sensor​​system​​and​​assess​​its​​ability​
​to​​detect​​instances​​of​​low​​blood​​oxygen.​​However,​​we​​are​​constrained​​by​​our​​ability​​to​​directly​
​measure opioid overdose-induced respiratory depression due to ethical and clinical factors.​
​In​ ​place​ ​of​ ​validating​ ​our​ ​sensor​ ​directly​ ​on​ ​patients​ ​experiencing​ ​an​ ​opioid​ ​overdose,​ ​we​
​propose​​a​​trial​​of​​our​​sensor​​on​​patients​​who​​have​​a​​medical​​condition​​in​​which​​they​​experience​
​hypoxic​ ​events.​ ​For​ ​example,​ ​patients​ ​with​ ​OSA​ ​experience​ ​intermittent​ ​episodes​ ​of​ ​airway​
​obstruction​​overnight,​​wherein​​relaxation​​of​​muscles​​in​​their​​throats​​causes​​soft​​tissue​​to​​collapse​
​and​ ​obstruct​ ​the​ ​airway.​ ​OSA​ ​patients​ ​may​​have​​multiple​​of​​these​​episodes​​per​​night,​​during​
​which​ ​their​ ​blood​ ​oxygen​ ​levels​ ​decrease​ ​below​ ​physiologically​ ​normal​ ​levels.​ ​In​ ​mild​ ​to​
​moderate​​cases​​of​​OSA,​​SpO2​​levels​​drop​​into​​the​​low​​80%​​range​​on​​average.​​11​​In​​severe​​cases,​
​it​​may​​drop​​as​​low​​as​​70%.​​12​ ​Patients​​experiencing​​opioid​​overdose​​will​​commonly​​have​​SpO2​
​levels below 90%.​
​1.2 Name and Description of the Investigational Product​
​Device name: DOVE Prototype​
​Device​​Description:​​The​​device​​is​​a​​de​​novo​​device​​called​​DOVE​​(​D​elivery​​of​​O​pioid​​agonists​
​for​ ​V​entilatory​ ​E​mergencies)​ ​Device.​​The​​data​​collected​​will​​be​​preliminary​​data​​for​​a​​future​
​study​​that​​aims​​to​​detect​​opioid​​overdose​​and​​inject​​naloxone.​​Naloxone​​will​​not​​be​​administered​
​during​ ​this​ ​trial.​ ​The​ ​DOVE​ ​prototype​ ​device​ ​is​ ​investigational.​ ​It​​has​​not​​been​​approved​​or​
​cleared by the FDA.​
​While​ ​the​ ​integration​ ​of​ ​a​ ​sensor​ ​to​ ​recognize​ ​opioid​ ​overdose​ ​and​ ​a​ ​direct​ ​reversal​ ​agent​
​response​​in​​a​​device​​is​​novel,​​there​​exist​​predicate​​devices​​that​​sense​​physiological​​variables​​and​
​administer​​a​​drug​​in​​response​​to​​changes​​in​​those​​variables.​​For​​example,​​the​​FreeO​​2​ ​wearable​
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​DOVE Prototype​​Trial​
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​device​​monitors​​hospitalized​​COPD​​patients​​by​​assessing​​SpO​​2​​.​​13​​In​​response​​to​​SpO​​2​​below​​the​
​target​​range,​​the​​device​​adjusts​​a​​valve​​that​​changes​​O​​2​ ​flow.​​Likewise,​​a​​sweat-based​​glucose​
​monitor (EOFlow) has been proposed in conjunction with transdermal glucose delivery.​​14​
​Device category:​
​Category B Device​
​Intended​ ​use:​ ​During​ ​this​ ​study,​ ​we​ ​will​ ​evaluate​ ​the​ ​functionality​ ​of​ ​the​ ​physiological​
​sensor components of our DOVE device prototype.​
​In​​the​​future,​​the​​final​​DOVE​​device​​would​​be​​a​​wearable​​device​​that​​has​​components​​that​​can​
​noninvasively​​sense​​overdose​​and​​administer​​an​​opioid​​antagonist.​​During​​this​​preliminary​​study,​
​we​​will​​assess​​whether​​the​​DOVE​​physiological​​sensor​​components​​are​​substantially​​equivalent​
​to​​a​​study-provided,​​FDA-approved​​FreeO​​2​ ​device​​in​​its​​continual​​assessment​​of​​a​​variable​​and​
​threshold​​for​​response​​during​​expected​​hypoxic​​episodes.​​We​​will​​also​​verify​​the​​accuracy​​of​​the​
​pulse​​oximeter​​across​​a​​variety​​of​​skin​​tones​​as​​assessed​​by​​the​​Pantone​​Skintone​​Guide​​®​​and​
​confirm the functionality of the accelerometer component of the device.​
​1.2.1​ ​Nonclinical Data​
​There​ ​is​ ​no​ ​animal​ ​model​ ​appropriate​ ​for​ ​testing​​the​​physiological​​sensor​​components​​of​​the​
​DOVE​​device,​​and​​therefore​​we​​have​​not​​done​​pre-clinical​​testing.​​Like​​FreeO​​2​​’s​​pulse​​oximetry,​
​DOVE​​would​​analyze​​physiologically​​associated​​waveforms​​and​​test​​whether​​those​​waveforms​
​elicit​​a​​threshold​​clinically​​significant​​hypoxia​​that​​could​​prompt​​the​​device​​to​​respond​​in​​future​
​iterations​​with​​injector​​capabilities.​​The​​DOVE​​prototype​​device​​used​​in​​this​​study​​will​​not​​have​
​an injector component and will not administer naloxone.​
​2​
​Study Objectives​
​2.1 Primary Objective​
​The​​primary​​objective​​is​​to​​assess​​the​​reasonable​​equivalence​​of​​the​​sensor​​portions​​of​​a​​DOVE​
​prototype​​to​​a​​study-provided,​​FDA-approved​​pulse​​oximeter.​​Our​​goal​​is​​to​​obtain​​functional​
​data using a DOVE prototype device.​
​2.2 Secondary Objectives​
​The​ ​secondary​ ​objective​​is​​to​​evaluate​​the​​effects​​of​​patient-level​​factors​​on​​data​​quality​​of​​a​
​DOVE​ ​prototype.​​Our​​goal​​is​​to​​collect​​variables​​known​​to​​affect​​data​​quality​​and​​real-world​
​practicality for FDA-approved pulse oximetry devices.​
​3​
​Investigational Plan​
​3.1​​General Design​
​The​​study​​will​​evaluate​​the​​functionality​​of​​a​​DOVE​​prototype​​biosensor​​in​​patients​​with​​clinical​
​suspicion​​of​​suffering​​hypoxic​​events.​​The​​study​​will​​obtain​​descriptive​​data​​on​​the​​use​​of​​the​
​DOVE​​device​​prototype​​and​​quantitative​​data​​to​​assess​​biofeedback​​sensation​​of​​this​​prototype​
​in​​comparison​​to​​a​​study​​FDA-approved​​sensor.​​Patients​​will​​be​​given​​the​​opportunity​​to​​review​
​the​ ​ICF​ ​and​ ​ask​ ​questions.​ ​Once​ ​consented,​ ​patients​ ​will​ ​be​ ​ask​ ​to​​wear​​a​​DOVE​​biosensor​
​prototype​​and​​an​​FDA-approved​​pulse​​oximeter.​​Examples​​of​​data​​collected​​are​​SpO​​2,​​including​
​hypoxic​​episodes​​experienced​​via​​pulse​​oximeter,​​motion​​(and​​lack​​thereof)​​via​​accelerometer.​
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​Version 1.2                                                     March 21, 2022​
​Due​​to​​known​​interference​​of​​skin​​tone​​with​​pulse​​oximetry​​sensor​​quality,​​participant​​skin​​tone​
​will​ ​be​​assessed​​at​​sites​​of​​pulse​​oximetry​​sensation​​(the​​back​​of​​the​​hand,​​wrist,​​and​​thumb)​
​using​​color​​patches​​from​​the​​Pantone​​Skintone​​Guide​​®.​​No​​patient​​will​​be​​excluded​​based​​on​
​the​​skintone.​ ​Patient​​comfort​​while​​wearing​​the​​device​​will​​be​​evaluated​​via​​5-point​​Likert​​scale​
​and​​open-ended​​qualitative​​questionnaire.​​This​​trial​​could​​enroll​​patients​​who​​are​​completing​​an​
​overnight​​study.​​The​​study​​will​​not​​exceed​​15hr​​for​​patients​​who​​are​​having​​an​​overnight​​study.​
​Clinical​ ​data​ ​will​ ​not​ ​be​ ​collected​ ​for​ ​the​ ​purposes​ ​of​ ​this​ ​study​ ​and​ ​naloxone​ ​will​ ​not​ ​be​
​administered.​ ​Device​​functionality​​will​​be​​assessed​​via​​a​​study-provided​​FDA-approved​​pulse​
​oximeter​ ​and​ ​DOVE​ ​prototype​ ​to​ ​be​ ​worn​ ​for​ ​the​ ​duration​ ​of​ ​the​ ​visit.​ ​This​ ​study​ ​could​
​potentially enroll patients during their overnight sleep test.​
​Devices​​will​​be​​collected​​at​​the​​end​​of​​the​​study​​visit.​​Comfort​​of​​the​​DOVE​​prototype​​will​​be​
​assessed​ ​via​ ​5-point​ ​Likert​ ​scale​ ​and​​open-ended​​qualitative​​questionnaire​​before​​participants​
​leave​​the​​sleep​​lab.​​No​​clinical​​data​​or​​patient​​identifiers​​will​​be​​collected​​as​​part​​of​​the​​study.​
​Pulse​ ​oximetry​ ​and​ ​accelerometry​ ​data​ ​will​ ​only​ ​be​ ​collected​ ​from​ ​SD​ ​cards​ ​housed​ ​within​
​study-provided devices.​
​3.1.1 Follow Up Phase​
​There​ ​is​ ​no​ ​follow-up​ ​period​ ​for​ ​the​ ​study.​ ​Participants​ ​will​ ​be​ ​provided​ ​with​ ​research​
​coordinator​ ​contact​ ​information​ ​to​ ​report​ ​adverse​ ​reactions​ ​to​ ​the​ ​wearing​ ​device,​ ​such​ ​as​
​irritation or rash.​
​3.2 Study Endpoints​
​3.2.1 Primary Study Endpoints​
​Primary​​endpoints​​are​​designed​​to​​assess​​device​​prototype​​functionality​​and​​examine​​reasonable​
​equivalence​ ​to​ ​FDA-approved​ ​devices​ ​already​ ​on​ ​the​ ​market.​ ​Examples​ ​of​ ​data​ ​collected​
​include:​
​●​ ​Assessing​​the​​effectiveness​​of​​the​​DOVE​​device​​at​​measuring​​biofeedback​​measurements​
​by​​correlating​​DOVE-recorded​​oximetry​​changes​​with​​hypoxic​​episodes​​measured​​by​​an​
​FDA-approved study sensor​
​●​ ​Patient​ ​movement​ ​(and​ ​lack​ ​thereof)​ ​throughout​ ​the​ ​night​ ​via​ ​DOVE​ ​prototype​
​accelerometer​
​3.2.2 Secondary Study Endpoints​
​Secondary​ ​endpoints​ ​are​ ​to​ ​evaluate​ ​the​ ​effects​ ​of​ ​patient-level​ ​factors​ ​on​ ​data​ ​quality​ ​of​ ​a​
​DOVE​ ​prototype.​​Our​​goal​​is​​to​​collect​​variables​​known​​to​​affect​​data​​quality​​and​​real-world​
​practicality for FDA-approved pulse oximetry devices. Examples of data collected are:​
​●​ ​Patient​​skin​​tone​​at​​the​​back​​of​​the​​hand,​​wrist,​​and​​thumb​​using​​color​​patches​
​from the Pantone Skintone Guide ®​
​●​ ​Patient​​comfort​​while​​wearing​​the​​device​​via​​5-point​​Likert​​scale​​and​​open-ended​
​qualitative questionnaire​
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​4. Study Population and Duration of Participation​
​Subjects​​will​​not​​be​​excluded​​based​​on​​race​​or​​skin​​tone.​​Due​​to​​known​​interference​​of​​skin​​tone​
​with pulse oximetry sensor quality, participant skin tone will be assessed at.​
​4.1​​Inclusion Criteria​
​●​ ​Males and Females​
​●​ ​21 years of age or older​
​●​ ​Suspected to suffer from hypoxic events.​
​●​ ​Able to provide informed consent​
​4.2​​Exclusion Criteria​
​●​ ​Pregnant​
​4.3​​Subject Recruitment​
​Subject​​recruitment​​will​​occur​​through​​Penn​​Medicine​​Faculty​​engagement,​​particularly​​referrals​
​from​ ​Penn​ ​physicians.​ ​The​ ​main​ ​approach​ ​for​ ​enrollment​ ​will​ ​be​ ​that​ ​the​ ​PI​ ​or​ ​study​ ​team​
​request​​referrals​​from​​Penn​​physicians.​​If​​the​​physician​​does​​not​​respond,​​the​​study​​team​​will​​not​
​approach the patient.​
​PI​​will​​approve​​study​​team​​members​​who​​can​​consent​​patients.​​EMR​​access​​will​​not​​be​​required​
​for this trial. Study team member approved by the PI will complete study procedures.​
​4.4​​Duration of Study Participation​
​Total​​duration​​of​​study​​participation​​for​​enrolled​​subjects​​will​​be​​no​​more​​than​​15​​hours​​from​
​study consent to device collection.​
​4.5​​Total Number of Subjects and Sites​
​Up to 20 subjects will be enrolled.​
​4.6​​Vulnerable Populations:​
​No vulnerable populations will be used in this study.​
​5​
​Study design phase​
​5.1​​Receipt​
​The​​design​​phase​​will​​consist​​of​​wearing​​the​​DOVE​​device.​​This​​study​​will​​only​​involve​​one​
​study​​visit.​​For​​study​​participant​​enrolled​​in​​the​​study​​at​​the​​same​​time​​they​​undergo​​a​​sleep​​test​
​they​​will​​be​​asked​​to​​wear​​the​​DOVE​​during​​for​​the​​entire​​duration​​of​​the​​sleep​​study.​​In​​the​
​event​​you​​are​​being​​enrolled​​on​​the​​day​​you​​are​​completing​​an​​overnight​​sleep​​test​​the​​visit​​will​
​last​​no​​more​​than​​20hrs.​​For​​all​​other​​study​​participants,​​they​​will​​wear​​the​​device​​overnight​​in​
​the​​conform​​of​​their​​home​​and​​return​​it​​the​​next​​day.​​The​​device​​may​​undergo​​minor​​changes​​in​
​response​​to​​functionality​​and​​subject​​comfort.​​The​​prototype​​device​​consists​​of​​a​​pulse​​oximeter​
​(oxygen​​sensor)​​and​​an​​accelerometer​​(movement​​sensor).​​The​​prototype​​device​​will​​be​​worn​​as​
​a​ ​combination​ ​of​ ​a​ ​ring​ ​on​ ​your​ ​finger​ ​and​ ​bracelet​ ​on​​your​​wrist​​while​​the​​study-provided,​
​FDA-approved pulse oximeter will be worn on your index finger.​
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​Before​ ​any​ ​study​ ​procedures​ ​are​​done​​the​​potential​​study​​participant​​will​​have​​ample​​time​​to​
​review​​the​​ICF​​and​​ask​​questions.​​Once​​the​​ICF​​has​​been​​signed​​the​​study​​team​​will​​assess​​the​
​patients​ ​skin​ ​tone​ ​and​ ​then​ ​set​ ​the​ ​patient​ ​with​ ​the​ ​device.​​The​​next​​day​​when​​the​​device​​is​
​collected​​the​​study​​team​​will​​administer​​a​​questionnaire.​​Study​​participants​​will​​be​​compensated​
​$25 for completing the trial​
​The​​clinical​​research​​team​​will​​maintain​​records​​logs​​regarding​​devices​​dispensed​​and​​returned​
​via​​device​​disposal​​logs.​​Devices​​will​​be​​labeled​​with​​a​​unique​​identifier.​​Study​​questionnaires​
​will be labeled by both device and participant ID numbers for data quality control.​
​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​
​A​​labeled​​prototype​​of​​the​​device​​as​​well​​as​​an​​FDA-approved​​pulse​​oximeter​​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.​ ​Study​ ​questionnaires​ ​will​ ​be​ ​labeled​ ​with​ ​the​
​unique identifier of the devices dispensed to ensure data quality control.​
​5.5​​Subject Compliance Monitoring​
​Subject​​are​​only​​required​​to​​wear​​the​​device​​for​​the​​duration​​of​​the​​visit.​ ​Information​​regarding​
​compliance​ ​and​ ​comfort​ ​will​ ​be​ ​included​ ​at​ ​device​ ​return​ ​as​ ​part​ ​of​ ​the​ ​open-ended​ ​patient​
​questionnaire.​
​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​
​Study Procedures​
​Screening​​/​​Device​
​dispensing​
​Device Collection​
​Review Inclusion/Exclusion Criteria​
​X​
​Informed Consent​
​X​
​Skin Tone​
​X​
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​Dispense​ ​FDA-approved​ ​sensor​ ​(Contec​
​CMS50DA Pulse Oximeter)​
​X​
​Dispense​ ​Investigational​ ​Product​ ​DOVE​
​prototype​
​X​
​Questionnaires​
​X​
​Collect​
​Investigational​
​Product​
​DOVE​
​prototype​
​X​
​Collect​
​FDA-approved​
​sensor​
​(Contec​
​CMS50DA Pulse Oximeter)​
​X​
​Assessment of possible AE​
​X​
​6.1 Screening and Baseline Data Collection​
​●​ ​Review of Inclusion/Exclusion criteria​
​●​ ​Sign informed consent​
​●​ ​Assess patient skin tone​
​●​ ​Dispense​ ​investigational​ ​product​ ​and​ ​study-provided​ ​FDA-approved​ ​pulse​
​oximeter​
​6.1.1 Device Collection​
​●​ ​Questionnaire about comfort of device​
​●​ ​Collect Investigational Product​
​●​ ​Assessment of possible Adverse Events​
​●​ ​that​ ​participants​ ​will​ ​be​ ​compensated​ ​with​ ​a​ ​$25​ ​gift​ ​card​ ​for​ ​completing​ ​the​
​study​
​6.2 Follow Up Phase of the Study​
​There​​will​​be​​no​​additional​​follow-up​​visit​​after​​completion​​of​​the​​study​​unless​​subjects​​call​​to​
​report adverse reactions to the device, such as irritation or rash.​
​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.​
​7​ ​Study Evaluations and Measurements​
​7.1 Medical Record Review​
​Referring doctor will assess inclusion criteria via medical record review.​
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​7.2 Pregnancy Testing​
​There will not be any pregnancy test. Study participants will be asked whether they are pregnant.​
​7.3 Laboratory Evaluations​
​There will not be any laboratory evaluations.​
​7.4 Other Evaluations, Measures​
​Female participants will be asked about pregnancy.​
​Skin Tone: Participant skin tone will be assessed according to the Pantone Skin Tone Guide ®.​
​Comfort:​ ​Participants​ ​will​ ​also​ ​be​ ​surveyed​ ​for​ ​their​ ​subjective​ ​comfort​ ​wearing​ ​the​ ​DOVE​
​prototype​​device.​​The​​interview​​and​​questionnaire​​will​​ensure​​that​​key​​topics​​such​​as​​compliance​
​and​​comfort​​are​​covered,​​while​​also​​allowing​​the​​subject​​to​​discuss​​issues​​and​​experiences​​with​
​the prototype device that the investigational team has not considered.​
​Possible​​Adverse​​Events:​​The​​interview​​and​​questionnaire​​will​​ensure​​that​​key​​adverse​​events,​
​such​ ​as​ ​irritation​ ​and​ ​rash,​ ​are​ ​covered​ ​while​ ​also​ ​allowing​​the​​subject​​to​​discuss​​issues​​and​
​experiences​​with​​the​​prototype​​device​​that​​the​​investigational​​team​​has​​not​​considered.​​Because​
​protected​ ​health​ ​information​ ​will​ ​not​ ​be​ ​collected​ ​at​ ​any​ ​point​ ​in​ ​the​ ​study,​ ​participants​ ​are​
​responsible​ ​for​ ​reporting​ ​any​ ​suspected​ ​long-term​ ​adverse​ ​events​ ​to​ ​a​ ​study-provided​ ​phone​
​number.​
​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​
​DOVE​ ​and​ ​FDA-approved​ ​device​ ​data​ ​will​ ​be​ ​collected​ ​in​ ​SD​ ​cards​ ​and​ ​stored​​in​​a​​locked​
​cabinet.​​Data​​will​​be​​maintained​​in​​locked​​files​​to​​which​​only​​authorized​​study​​personnel​​will​
​have​ ​access​ ​and​ ​analyzed​ ​using​ ​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​ ​in​ ​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.​
​8.1​​Primary Endpoint​
​As​ ​the​ ​primary​ ​objectives​ ​are​ ​designed​ ​as​ ​a​ ​functionality​ ​study,​ ​no​ ​power​ ​analysis​ ​will​ ​be​
​performed. The sample size is one of convenience and limited by resources.​
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​8.2​​Secondary Endpoints​
​The​​secondary​​endpoints​​related​​to​​comfort-level​​factors​​are​​descriptive​​and​​designed​​to​​further​
​prototype​​designs​​for​​the​​DOVE​​prototype​​for​​later​​device​​iterations.​​Skin​​tone​​will​​be​​evaluated​
​as a measure of the function of the SpO​​2​​sensor as​​part of the primary endpoint.​
​8.3​​Sample Size and Power Determination​
​As​ ​the​ ​primary​ ​objectives​ ​are​ ​designed​ ​as​ ​a​ ​functionality​ ​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,​ ​functional​ ​biosensor​ ​components​ ​of​ ​the​ ​DOVE​ ​device​ ​will​ ​be​
​analyzed​​against​​a​​study-provided,​​FDA​​approved​​SpO​​2​​sensor.​​Skin​​tone​​will​​be​​incorporated​​as​
​a​​factor​​of​​SpO​​2​​function​​to​​ensure​​the​​device​​can​​reasonably​​detect​​hypoxia​​across​​a​​diverse​​user​
​base.​ ​Comfort,​ ​design​ ​preference,​ ​and​ ​other​ ​individual-level​ ​factors​ ​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​ ​in​ ​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.​
​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​
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​●​ ​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.​
​9.2 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​.​
​9.2.1 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.​
​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​
​personnel​ ​will​ ​evaluate​ ​for​ ​lesions​ ​at​ ​the​ ​site​ ​of​​placement​​on​​the​​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​
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​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.​
​9.5 Follow-up reports​
​There will be no additional follow-up visit after completion of the study.​
​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​ ​SAEs​ ​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.​
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​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.​
​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.​
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​●​ ​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.​
​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.​
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​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.​ ​For​ ​subjects​ ​that​ ​have​ ​revoked​ ​authorization​ ​to​ ​collect​ ​or​ ​use​ ​PHI,​ ​attempts​
​should​​be​​made​​to​​obtain​​permission​​to​​collect​​at​​least​​vital​​status​​(i.e.​​that​​the​​subject​​is​​alive)​​at​
​the end of their scheduled study period.​
​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​​pulmonary​​faculty.​​Research​​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​​patient​​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.​
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​This​​will​​include​​data​​management​​and​​procedures​​for​​maintaining​​confidentiality​​and​​subject​
​safety.​​Study​​team​​will​​link​​PHI​​to​​subject​​identifiers​​for​​monitoring​​and​​auditing​​purposes.​​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​ ​performed​ ​nightly.​ ​No​ ​protected​ ​health​
​information​​linking​​the​​assigned​​unique​​identifier​​to​​the​​subject​​identity​​will​​be​​collected.​​Study​
​files​​and​​SD​​cards​​from​​the​​study​​devices​​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.​
​The​​DOVE​​device​​will​​record​​SpO2​​and​​Heart​​rate​​values​​off​​the​​participants​​while​​storing​​the​
​encrypted​​data​​on​​local​​storage​​(micro​​SD​​card)​​.​​The​​data​​collected​​will​​not​​allow​​us​​to​​identify​
​the​ ​participants​ ​and​ ​is​ ​encrypted​ ​using​ ​AES​ ​encryption​ ​which​ ​is​​FIPS​​140-2​​complaint.​​The​
​collected data will be then analyzed on a HIPAA-certified laptop.​
​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.​
​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.​
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​16 Risks​
​Potential​ ​study​ ​risks​ ​include​ ​the​ ​accidental​ ​breach​ ​of​ ​confidential​ ​patient​ ​health​ ​information​
​during​ ​patient​ ​enrollment.​ ​Precautions​ ​will​ ​be​ ​taken​ ​to​ ​ensure​ ​that​ ​strict​ ​confidentiality​ ​is​
​maintained.​​Study​​team​​will​​link​​PHI​​to​​subject​​identifiers​​for​​monitoring​​and​​auditing​​purposes.​
​This​ ​risk​ ​has​ ​been​ ​mitigated​ ​by​ ​extensive​ ​privacy​ ​protection​ ​protocols,​ ​a​ ​highly​ ​secure​ ​data​
​storage​ ​system​ ​at​ ​Penn​ ​Medicine,​ ​and​ ​a​ ​plan​ ​to​​exclude​​identifiers​​from​​the​​data​​entirely.​​In​
​addition,​ ​all​ ​study​ ​personnel​ ​will​ ​be​ ​held​ ​to​ ​high​ ​standards​ ​of​ ​upholding​ ​confidentiality​ ​and​
​safeguarding​ ​patient​ ​privacy.​ ​No​ ​protected​ ​health​ ​information​ ​linking​ ​the​ ​assigned​ ​unique​
​identifier​ ​to​ ​the​ ​subject​ ​identity​ ​will​ ​be​ ​collected.​ ​To​ ​ensure​ ​that​ ​patient​ ​confidentiality​ ​is​
​preserved,​​though,​​data​​will​​be​​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​ ​identifying​ ​information,​ ​such​ ​as​ ​identifying​ ​answers​ ​to​ ​open-ended​ ​questions,​
​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.​
​The​ ​risks​ ​of​ ​the​ ​wearable​ ​devices​ ​is​​that​​patients​​will​​wear​​a​​novel​​device​​prototype​​for​​this​
​study. There is a risk of irritation or rash developing at the site of device placement.​
​17 Benefits​
​There are no direct expected benefits to the subjects.​
​Long-term,​​the​​technology​​aims​​to​​improve​​the​​quality​​of​​life​​for​​patients​​at​​high​​risk​​of​​fatal​
​opioid overdose.​
​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​ ​meet​​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 withdraw from the study.​
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​18 Study Finances​
​18.1 Funding Source​
​The study will be financed through the Coulter foundation.​
​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.​
​It​​is​​unlikely​​that​​this​​particular​​study​​will​​lead​​to​​publication​​as​​it​​is​​intended​​for​​baseline​​data​
​on​​the​​device.​​This​​foundational​​study​​will,​​however,​​be​​seminal​​to​​future​​studies​​that​​may​​be​
​published as the device reaches its final development.​
​20 References​
​1.​​Centers​​for​​Disease​​Control​​and​​Prevention.​​Overdose​​Deaths​​Accelerating​​during​​COVID-19.​
​(2020).​
​2.​ ​Centers​ ​for​ ​Disease​​Control​​and​​Prevention.​​Data​​Brief​​329:​​Drug​​Overdose​​Deaths​​in​​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.​​Van​​der​​Schier,​​R.​​et​​al.​​Opioid-induced​​respiratory​​depression:​​reversal​​by​​non-opioid​​drugs.​
​F1000Prime Rep, (2014); 6: 79.​
​8. DrugBank Online. Naloxone. (2021).​
​9.​​Leonard​​Davis​​Institute​​of​​Health​​Economics.​​Expanding​​Access​​to​​Naloxone:​​A​​Review​​of​
​Distribution Strategies. (2019).​
​10.​ ​Ogeil​ ​R.P.​ ​et​ ​al.​ ​Pharmaceutical​ ​opioid​ ​overdose​ ​deaths​ ​and​ ​the​ ​presence​ ​of​ ​witnesses.​
​International Journal of Drug Policy. (2018);55:8-13.​
​11.​​Charbonneau,​​M.​​et​​al.​​Changes​​in​​obstructive​​sleep​​apnea​​characteristics​​through​​the​​night.​
​Chest. (1994); 106:6,1695-1701.​
​12.​ ​Wali,​ ​S.O.​ ​et​ ​al.​ ​The​ ​correlation​ ​between​ ​oxygen​ ​saturation​ ​indices​ ​and​ ​the​ ​standard​
​obstructive sleep apnea severity. Annals of Thoracic Medicine. (2020);15(2):70-75.​
​13.​​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).​
​14.​​Lee,​​H.​​et​​al.​​Wearable/disposable​​sweat-based​​glucose​​monitoring​​device​​with​​multistage​
​transdermal drug delivery module. Sci. Adv.​​3​, e1601314​​(2017).​
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