Disrupted Sleep and Concurrent Ectopy or Atrial Fibrillation
Phase: NA
Conditions: Obstructive Sleep Apnea, Premature Ventricular Contraction (PVC), Atrial Fibrillation (AF), Premature Atrial Contraction
Sponsor: University of California, San Francisco

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Clinical Research Protocol 
Disrupted Sleep and Concurrent Ectopy or Atrial Fibrillation (DISCRETE AF) 
 
Protocol Number: 
1.1 
Version Date: 
June 03, 2025 
Funding Organization: 
UCSF Cardiology and the Heart Rhythm Society 
Principal Investigator: 
Name: Gregory M Marcus, MD, MAS 
 
Telephone: 415-476-3450 
E-mail: greg.marcus@ucsf.edu  
 
Name: Jean Jacques Noubiap, MD, PhD 
 
Telephone: 415-476-3450 
E-mail: jeanjacques.noubiapnzeale@ucsf.edu 
Mentor: 
Name: Gregory M Marcus, MD, MAS 
 
Telephone: 415-476-3450 
E-mail: greg.marcus@ucsf.edu 
Co-Investigators  
Name: Jolie Chang, MD, Sleep Surgery, UCSF 
Name: Catherine Lee, PhD, Department of Epidemiology and 
Biostatistics, UCSF  
Clinical Research 
Coordinators 
Name: Hannah Hninyi Oo 
Name: Gabrielle C. Montenegro 
 
Approval: 
 
 
 
Principal Investigator or Sponsor Signature (Name and Title)                 Date 
 
 
The information in this document may not be disclosed unless federal or state law or regulations 
require such disclosure.  Subject to the foregoing, this information may be disclosed only to those 
persons involved in the study who have a need to know, with the obligation not to further disseminate 
this information. 

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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study participants enrolled under my supervision and 
ensuring complete and timely information, as outlined in the protocol.  It is understood 
that all information pertaining to the study will be held strictly confidential and that this 
confidentiality requirement applies to all study staff at this site. Furthermore, on behalf of 
the study staff and myself, I agree to maintain the procedures required to carry out the 
study in accordance with accepted Good Clinical Practice principles and to abide by the 
terms of this protocol. 
 
Protocol Number: 2.0 
 
Protocol Title:  Disrupted Sleep and Concurrent Ectopy or Atrial Fibrillation (DISCRETE 
AF) 
 
 
Protocol Date: 07 May 2025 
 
 
 
 
Investigator Signature  
 
Date 
 
Print Name and Title 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
1 
INTRODUCTION ............................................................................................................ 8 
1.1 
BACKGROUND ........................................................................................................... 8 
1.2 
SIGNIFICANCE ............................................................................................................ 8 
2 
STUDY OBJECTIVES ..................................................................................................... 9 
2.1 
GENERAL OBJECTIVE ...................................................................................................... 9 
2.2 
SPECIFIC OBJECTIVES ...................................................................................................... 9 
3 
STUDY DESIGN .............................................................................................................. 9 
3.1 
STUDY OVERVIEW .......................................................................................................... 9 
4 
CRITERIA FOR EVALUATION .................................................................................... 10 
4.1 
PRIMARY ENDPOINT ....................................................................................................... 10 
4.2 
SECONDARY ENDPOINTS ................................................................................................. 10 
5 
PARTICIPANT SELECTION ......................................................................................... 10 
5.1 
INCLUSION CRITERIA ...................................................................................................... 10 
5.2 
EXCLUSION CRITERIA ..................................................................................................... 10 
6 
STUDY INTERVENTIONS ............................................................................................ 10 
6.1 
HYPOGLOSSAL NERVE STIMULATION THERAPY .................................................................. 10 
6.2 
METHOD OF ASSIGNING PARTICIPANTS TO INTERVENTIONS .................................................. 11 
6.3 
MEASURES OF INTERVENTION COMPLIANCE ...................................................................... 11 
7 
STUDY PROCEDURES ................................................................................................. 11 
7.1 
PARTICIPANT RECRUITMENT ............................................................................................ 11 
7.2 
MOBILE STUDY ACTIVITIES : MOSIO FOR RESEARCH .................................................................. 11 
7.3 
ECG MONITOR: ZIO® XT PATCH EVENT MONITOR ........................................................... 11 
7.4 
HOME SLEEP APNEA TEST .................................................................................................. 12 
7.5 
TEXT MESSAGING SERVICE ................................................................................................. 12 
7.6 
ENROLLMENT VISIT (PRE-SCREENING/PRE-CONSENT) ......................................................... 12 
7.7 
BASELINE VISIT (BEFORE DAY 1) ..................................................................................... 12 
7.8 
RANDOMIZATION AND MONITORING (DAY 1-14) ................................................................ 13 
7.9 
ASSESSMENT OF SLEEP QUALITY ........................................................................................... 13 
7.10 
MONITORING CLOSE-OUT VISIT (DAY 15+) ....................................................................... 13 
8 
RISK AND BENEFIT ASSESSMENT .............................................................................. 14 
8.1 
RISKS ........................................................................................................................... 14 
8.2 
BENEFITS ...................................................................................................................... 14 
8.3 
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS .............................................................. 14 
9 
DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS .................................. 15 
9.1 
EARLY DISCONTINUATION FROM RANDOMIZATION ............................................................. 15 
9.2 
WITHDRAWAL OF PARTICIPANTS FROM THE STUDY ............................................................. 16 
9.3 
REPLACEMENT OF PARTICIPANTS ..................................................................................... 16 
10 
STATISTICAL METHODS AND CONSIDERATIONS ..................................................... 16 
10.1 
SAMPLE SIZE AND RANDOMIZATION ................................................................................. 16 
10.2 
STATISTICAL ANALYSIS PLAN (SAP) AND OUTCOME ASSESSMENT ....................................... 16 

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10.3 
INTENTION-TO-TREAT (ITT) ............................................................................................ 16 
11 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ............................. 17 
11.1 
PROTOCOL AMENDMENTS ............................................................................................... 17 
11.2 
INFORMED CONSENT FORM ............................................................................................. 17 
12 
REFERENCES .............................................................................................................. 17 
 

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LIST OF ABBREVIATIONS 
AF 
atrial fibrillation 
CFR 
Code of Federal Regulations 
ECG 
electrocardiogram 
HGNS 
Hypoglossal nerve stimulation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
PACs 
Premature atrial contractions 
PVCs 
Premature ventricular contractions 

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PROTOCOL SYNOPSIS 
TITLE 
Disrupted Sleep and Concurrent Ectopy or Atrial Fibrillation 
(DISCRETE AF) 
SPONSOR 
Investigator-initiated 
FUNDING 
ORGANIZATION 
UCSF Cardiology and the Heart Rhythm Society 
NUMBER OF SITES 
1 
RATIONALE 
To examine, in a randomized fashion to allow inference of causal 
effects, the acute relationship between sleep disruption and atrial and 
ventricular ectopy.  
STUDY DESIGN 
This is a prospective, randomized, case-crossover study. 
GENERAL 
OBJECTIVE 
To assess the acute effects of sleep disruption on clinically relevant 
cardiac ectopy pertinent to atrial fibrillation (AF). 
SPECIFIC 
OBJECTIVES 
Primary:  
• To assess the effect of sleep disruption on daily number of cardiac 
ectopic beats. 
Secondary: 
• To assess the effect of sleep disruption on daily number of 
premature atrial contractions (PACs). 
• To assess the effect of sleep disruption on daily number of 
premature ventricular contractions (PVCs). 
• To assess the effect of sleep disruption on daily number of AF 
episodes.  
NUMBER OF 
PARTICIPANTS 
100 
PARTICIPANT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
• Age 21 years or older 
• Have a hypoglossal nerve stimulation (HGNS) device 
implanted for obstructive sleep apnea and followed up at 
UCSF 
• Are willing to abstain from using the HGNS device for no 
more than two consecutive days as instructed over the 14-day 
trial period  
• Able and willing to provide written informed consent 
Exclusion Criteria: 
• Currently pregnant or trying to get pregnant 
• Are currently taking Class 1 or 3 anti-arrhythmic medications 
• Have a history of permanent AF or expected to have AF 
throughout the study period  

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• Have congenital heart disease 
• Are >40% ventricular paced  
• Are unable to read or sign to provide informed consent 
STUDY DURATION 
Participants will participate for approximately 2 weeks.  
• Randomization and monitoring: up to 2 weeks. 
PROCEDURE 
After being fitted with an automatically recording 
electrocardiographic monitor, the HGNS device will then be “on” 
versus “off” (where “off” is turning off the HGNS device for one 
night and “on” is turning on the HGNS device) over the ensuing 14 
days. Participants will be randomized to “off-on” versus “on-off” 
periods, assuring no more than two consecutive days of either device 
use or not. Electrocardiographic monitoring data will be used to assess 
for endpoints.  
PRIMARY ENDPOINT The daily number of cardiac ectopic beats 
SECONDARY 
ENDPOINTS 
• The daily number of PACs  
• The daily number of PVCs 
• The daily presence versus absence of AF episodes ≥ 30 
seconds 
 
STATISTICS 
Primary Analysis Plan 
Our primary analyses will employ intention-to-treat principles, 
examining randomization assignment as the primary predictor.  
Rationale for Number 
of Participants 
Using a two-tailed alpha of 0.05, we estimate we will need 100 
participants to have 80% power in intention-to-treat analyses 
comparing nights on and off HGNS to detect a 2% increase in cardiac 
ectopy. 
 

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1 
INTRODUCTION 
1.1 
BACKGROUND 
Sleep disorders and poor sleep are a major public health problem owing to their 
prevalence and adverse effects. One health condition that sleep disorders have long been 
implicated in is the development of AF. AF is the most common sustained cardiac 
arrhythmia. In a recent study, we estimated that the current US national prevalence of 
diagnosed AF is at least 10.55 million, comprising 4.48% of the adult population, 
substantially exceeding prior projections.1 AF is a leading cause of stroke, reduces quality 
of life, increases risks of myocardial infarction and dementia,2 and results in > $28 billion 
in US healthcare expenditures annually.3  
The relationship between poor sleep and incident AF was initially attributed to a 
common association with obstructive sleep apnea (OSA). However, emerging evidence 
suggests that chronic sleep disruption independent of OSA may play a role in the 
development of AF. Indeed, work largely from our group has revealed that abnormal sleep 
characteristics including frequent nighttime awakening, less rapid eye movement (REM) 
sleep, and a diagnosis of insomnia may predict incident AF, even after adjustment for 
OSA.4, 5 Furthermore, studies of the circadian variation of arrhythmia onset patterns in 
patients with AF have shown a nocturnal predominance, suggesting that nocturnal events 
such a disrupted sleep may be arrhythmogenic.6, 7 Whereas the available evidence mostly 
support chronic sleep disruption as a risk factor for incident AF, less is known about the 
near-term risk of a discrete AF episode following a night of disrupted or poor-quality 
sleep. 
1.2 
SIGNIFICANCE 
Acute lack of sleep has been identified by patients as one of the most common 
triggers of AF.8 In the Individualized Studies of Triggers of Paroxysmal Atrial Fibrillation 
(I-STOP-AFib) randomized clinical trial conducted by our group, poor sleep was 
associated with an immediately increased risk for self-reported AF episodes, and a dose-
response relationship existed such that progressively worse sleep was associated with 
longer episodes of AF the next day.9 These data suggest that sleep quality may be a 
potentially modifiable, immediate, trigger of AF. However, in this study, both sleep 
quality and AF episodes were subjectively assessed based on self-report, highlighting the 
need for studies of the relationship of poor sleep and AF episodes using objective 
measurements.  
Given evidence regarding chronic effects of sleep disruption, why is it important to 
study acute effects as proposed here? There are several reasons. First, while long-term risk 
factors for AF have been well-established, there is growing interest among both patients 
and expert clinicians and investigators that understanding acute triggers of AF are 
important.8, 10, 11 Second, patient behavior is generally more strongly motivated or 
changed at the prospect of immediate rather than delayed effects.12, 13 Third, the study of 
such acute effects may provide more precision and more compelling data regarding causal 
effects—for example, randomized trials of sleep apnea treatment of AF have thus far 
failed to demonstrate meaningful chronic effects.14, 15 Of note, those studies relied on 

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external machines to treat sleep apnea, devices that are notoriously unwieldly and subject 
to poor patient compliance.  
This will be the first randomized case-crossover assessment to reveal immediate 
relationships between sleep disruption and more frequent clinically relevant common 
cardiac arrhythmias pertinent to and potentially including AF episodes. Specifically, 
premature atrial contractions (PACs) are the most potent predictor of AF.16-18 Other 
potentially important arrhythmias are premature ventricular contractions (PVCs), a higher 
frequency of which is clinically relevant as it predicts future heart failure.19, 20 Because 
everyone experiences PACs and PVCs, use of continuously worn ECG monitors that 
quantify such common ectopy can be used to harness sufficient power to evaluate 
clinically relevant outcomes as done in the Coffee and Real-time Atrial and Ventricular 
Ectopy (CRAVE) study.21 
Compelling evidence of the direct impact of sleep disruption on discrete AF 
episodes would be directly and immediately relevant to clinical care of our patients. In 
fact, identifying near-term triggers of AF is a high priority for patients with AF and may 
effectively determine lifestyle modifications that can meaningfully affect the risk of an 
arrhythmia occurrence.8, 10, 22  
 
2 
STUDY OBJECTIVES 
2.1 
General Objective 
This randomized case-crossover trial aimed to test the hypothesis that sleep disruption 
acutely increases clinically relevant cardiac ectopy pertinent to AF, specifically the 
frequency of PACs and PVCs.  
2.2 
Specific Objectives 
• Primary: 
To assess the effect of sleep disruption on daily number of cardiac ectopic beats.  
• Secondary: 
o To assess the effect of sleep disruption on daily number of PACs.  
o To assess the effect of sleep disruption on daily number of PVCs.  
o To assess the effect of sleep disruption on the daily presence versus absence of 
AF.  
 
 
3 
STUDY DESIGN 
3.1 
Study Overview 
This is a single center, non-blinded, prospective, randomized, case-crossover trial, where 
100 participants will be randomized to turning “on” or “off” their hypoglossal nerve 
stimulation (HGNS) device each day of a 14-day monitoring period. Participants will wear 
an automatically recording electrocardiographic (ECG) monitor and utilize a text 
messaging software for surveys and data capture. Participants will also share their sleep 
information from their HGNS device with the investigators. 

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4 
CRITERIA FOR EVALUATION 
4.1 
Primary Endpoint 
The daily number of ectopic beats (per 24-hour period). 
4.2 
Secondary Endpoints 
• The daily number of PACs 
• The daily number of PVCs 
• The daily presence of AF  
 
5 
PARTICIPANT SELECTION 
5.1 
Inclusion Criteria 
Participants must meet all the following to be eligible: 
• Are age 21 years or older 
• Have a HGNS device implanted for OSA and followed up at UCSF 
• Are willing to abstain from using the upper airway stimulation device for no more 
than two consecutive days as instructed over the 14-day trial period  
• Able and willing to provide written informed consent 
5.2 
Exclusion Criteria 
• Currently pregnant or trying to get pregnant 
• Are currently taking class 1 or 3 anti-arrhythmic medications 
• Have congenital heart disease 
• Ventricular pacing >40% 
• Are unable to read or sign to provide informed consent 
 
6 
STUDY INTERVENTIONS 
6.1 
Hypoglossal Nerve Stimulation Therapy 
HGNS is performed by the Inspire Upper Airway Stimulation (Inspire Medical Systems, 
Inc., Golden Valley, Minnesota, US), a fully implanted system that is placed under the 
skin of the neck and chest. A remote system can be used to turn the device on or off at 
nighttime. When sleeping, the device stimulates the tongue, increasing muscle tone and 
opening the airway in sleep. HGNS has been shown to lead to significant improvements in 
sleep apnea, sleepiness, and quality of life in patients with OSA.23, 24 The use of HGNS by 
these patients significantly improves their sleep with a reduction in sleep disruption, and 
those with the implant have met all clinical indications for the device. No participant will 
have a device placed solely for the purpose of study participation and all will already have 

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a device implanted per standard clinical indications. A night on HGNS will be considered 
as reduced sleep disruption, whereas a night off HGNS will be considered one with more 
sleep disruption.  
6.2 
Method of Assigning Participants to Interventions 
After being fitted with an automatically recording electrocardiographic monitor, the 
HGNS device will then be “on” versus “off” (where “off” is turning off the HGNS device 
for one night and “on” is turning on the HGNS device) over the ensuing 14 days. 
Participants will be randomized to “off-on” versus “on-off” periods, assuring no more 
than two consecutive days of either device use or not—this helps assure equal or near-
equal days for each assignment even with truncated follow-up; and maximizes the number 
of switches between the two to assure examination of acute effects rather than chronic, 
cumulative effects.  
6.3 
Measures of Intervention Compliance 
Compliance with intervention assignments will be assessed based on review of daily 
reports. These reports could be accessed through the Inspire® app that allows patients to 
share sleep therapy data with their clinicians, or alternatively, downloaded during a clinic 
visit. 
 
7 
STUDY PROCEDURES  
7.1 
Participant Recruitment 
Potential participants will be referred to us from the UCSF Sleep Surgery Division where 
>200 patients with HGNS therapy are being followed (and implants continue to be 
placed).  Research personnel will contact these potential participants to schedule an initial 
in-person Enrollment Visit at Parnassus, or for a remote Enrollment Visit via video 
conference, with a study coordinator. During the Enrollment Visit, study staff will confirm 
that the participant is eligible for the study via an eligibility survey. Study staff will then 
review the study terms and obtain informed consent from eligible, interested participants. 
Study participation is anticipated to be 16 days with two in-person or remote visits 
occurring at study commencement and termination (Baseline and Termination). The 
participant may withdraw voluntary participation at any time.  An early termination visit 
should be done if a participant chooses to discontinue participation prior to study 
completion. 
7.2 
Mobile Study Activities: Mosio for Research 
We will use the Mosio platform, a text messaging software that connects to REDCap for 
digital surveys, to facilitate single subject case-crossover experiments.  
7.3 
ECG Monitor: ZIO® XT Patch Event Monitor 
Each participant will be equipped with a ZIO® XT Patch (iRhythm, San Francisco), 
which is a 2" by 3" sticky patch. This external cardiac event monitor utilizes validated 

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algorithms to automatically detect heart rhythm disturbances independent of heart rate. 
The device records every heartbeat, providing a continuous Holter function. The ZIO® 
XT Patch is produced by iRhythm and mailed in a prepaid box back to iRhythm for 
analysis. iRhythm will not receive any patient identifying information.  
7.4 
Home Sleep Apnea Test 
Each participant will undergo two consecutive days of home sleep apnea recording using 
the WatchPAT® ONE-M Home Sleep Apnea Test (Itamar Medical, Caesarea). The 
WatchPAT® ONE-M is a disposable, portable, home sleep apnea test and diagnostic 
device that uses peripheral arterial tonometry, an approved measure that has an 89% 
correlation with polysomnography, the reference standard to diagnose and assess the 
severity of OSA.25 We will collect data on the Apnea/Hypopnea Index (AHI), the number 
of apnea episodes throughout the night, pulse oximetry and heart rate. The manufacturer, 
Itamar Medical, will not receive any patient identifying information.  
7.5 
Text Messaging Service 
We will use Mosio, text messaging software for clinical research that will deliver daily 
text reminders with surveys to the participants. Participants will receive a text welcoming 
them to the study upon completing the Enrollment and Baseline Visits, and daily texts 
with relevant study surveys throughout the monitoring period.   
7.6 
Enrollment Visit (Pre-Screening/Pre-Consent) 
The Enrollment Visit (on or before Day 0) takes place on the same day as or prior to the 
day of the Baseline Visit and is aimed for: 
• 
Pre-screen potential participants by eligibility criteria 
• 
Schedule Baseline Visit 
At this point, participants are still free to use their HGNS as usual. 
7.7 
Baseline Visit (Before Day 1) 
Study staff will meet the study participant at UCSF (i.e. in the Clinical Research Center) 
or remotely through a phone/video call. If the participant is eligible per the study’s 
inclusion and exclusion criteria, the study staff will review and obtain informed consent 
At this visit, the study staff will also collect the participant’s contact information. 
Additionally, the study staff will administer baseline surveys including demographics, bits 
(such as alcohol, smoking, cannabis use), medical conditions, medications inventory, 
Epworth Sleepiness Scale, Insomnia Severity Index and Functional Outcomes of Sleep 
Questionnaire. 
At the Baseline Visit, the study staff, all of whom are trained, will fit the provided 
devices for an in-person participant or direct self-administration for a remote participant, 
and instruct the participant on device application and care. The study staff will inform the 
participant of relevant risks pertaining to potential skin irritation from the adhesive on the 
devices and will also explain relevant information pertaining to loss of privacy in the 
study (see section 8.1).  

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After completion of study device education and fitting, the study staff will schedule 
the participant’s final Termination Visit (Day 15+). Participants are still free to use their 
HGNS device as usual on the day of the Baseline Visit. 
7.8 
Randomization and Monitoring (Day 1-14) 
At 08:00 AM on the first day (Day 1), the participant will receive a text or push 
notification from a mobile app or text messaging service with instructions for the same 
day’s randomization. Their first reminder regarding their randomization will be at 08:00 
PM on Day 1. During the study (Day 1-14), participants will receive two text or push 
notifications (AM and PM) each day: 
1. 08:00 AM: Instructions on the present day’s randomization, in addition to daily 
surveys on randomization compliance and sleep quality. 
2. 08:00 PM: Reminder of instructions on the present day’s randomization.  
At 08:00 AM on Day 15 participants will complete the final compliance survey and 
will be reminded to resume their normal HGNS use. 
“On” day messages will instruct participants to use their HGNS device and on “off” 
days, participants will be instructed to not used them. To avoid >2 consecutive days with 
or without using their device, participants will be randomized in pairs of either "off one 
day and on the next day" or "on one day and off the next day".  
Each participant will also undergo two consecutive days of home sleep apnea 
recording using the WatchPAT® ONE-M Home Sleep Apnea Test, ideally during the first 
days of participation.   
Throughout the study period (Day 1-14), the participants should continuously wear 
their ECG monitor. 
7.9 
Assessment of sleep quality 
The sleep quality on the preceding night will be assessed via a mobile app-based survey 
and categorized as “amazing,” “good,” “average,” “bad,” or “horrible.” As previously 
reported, the choice of terminology and method of data input were developed in 
collaboration with patients to prioritize capture of information believed in their opinion to 
be important, maximize ease of understanding, and facilitate daily use.9 
7.10 Monitoring Close-Out Visit (Day 15+) 
During the Termination Visit (Day 15+) on Day 15 or later, the study staff will meet the 
study participant at UCSF (i.e. in the Clinical Research Center) or remotely via 
phone/video call at the time specified by the study participant. The study staff will remove 
or remotely instruct the participants on how to remove the ECG monitor.  
  

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8 
RISK AND BENEFIT ASSESSMENT 
8.1 
Risks 
Potential risks of the study include the following: 
 
• Small risk of loss of privacy: Data that the participant provides to the study may be 
sensitive and could be embarrassing to participants or lead to insurance coverage 
problems if it were leaked (e.g., obesity or very high blood pressure).  
• Financial risk: Participating in the study may make participants want to access the 
healthcare system more often or purchase health-related devices to link to the 
study, and that all costs money.  
• Risks of study sensors: Allergy to the adhesive used for the event monitor 
electrodes can lead to a rash, pruritus, and/ or painful irritation. Topical steroids 
will be provided if needed and participants will be provided an option to decline if 
they are concerned given past experience. As with previous studies, sensors may 
be moved and/ or not worn if irritation is not tolerable (in which case, late screen-
failures and alternative/ additional participants may be used for replacement).  
• Risks of HGNS withdrawal: as expected participants may experience an increase in 
sleep disruption on the days their device is off, potentially leading to a relapse of 
their OSA symptoms. There should be no long-term effects of therapy withdrawal. 
Indeed, a previous study showed that 1-week continuous withdrawal of therapeutic 
HGNS results in acute worsening of both objective and subjective measures of 
sleep and breathing, but with return of the positive therapeutic effects upon 
resuming therapy.26 To limit the acute negative impact of the withdrawal therapy 
on their well-being, no participant will be instructed to turn off their device more 
than 7 out of the 14 participation days. It is also part of standard of care 
8.2 
Benefits 
There are no direct benefits for participating in this study. However, the knowledge gained 
from this study may help better understand the mechanisms underlying AF occurrence. 
Furthermore, compelling evidence of the direct impact of sleep disruption on discrete AF 
episodes would be directly and immediately relevant to clinical care of patients with AF. 
8.3 
Assessment of Potential Risks and Benefits 
The Investigator considers protection against risks to be a major responsibility. The 
following strategies are pursued to minimize risks:  
• 
Risk of loss of privacy: Storage of study data in a secure database. 
o Password-protected log-in will be required to see study data. A password 
recovery system will be set up to allow participants to input both the 
question and answer for a “hint” that can be provided by the website.  
o An explicit Privacy Statement is included in the Informed Consent 
document and posted to the study website to fully inform participants.  
o An audit trail will record all logins and any changes to study data.  

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o If an event occurs that threatens participant privacy or data security, we 
will notify our IRB immediately and fully document the occurrence.  
o E-mails, app notifications, and texts to the study participants are for the 
sole purpose of engagement and retention. No sensitive health information 
will be sent via e-mail to a participant.  
• 
Financial risk: Participants are informed about the financial risk and encouraged 
not to see a healthcare provider (for which they might have to pay) solely for the 
purpose of collecting data for the study.  
• 
Online surveys and linkage to health data from sensors or web applications: Study 
coordinators are available (by email and by phone) to answer any uncomfortable 
questions about surveys, study devices, or other study activities that arise.  
• 
Risks of study sensors: Hypoallergenic adhesive will be provided to patients that 
develop any rash, pruritus, or painful irritation that develops. Participants will also 
be prescribed oral Benadryl and/ or topical steroid cream if necessary. Finally, 
they will have the option to discontinue participation if an adhesive reaction is not 
tolerable.  
• 
Risks of HGNS withdrawal: The study is designed specifically to avoid 
participants to have their device turned “off” more than 7 out of the 14 
participation days, with no two consecutive days “off”. This will be accomplished 
by a randomization to “off-on” versus “on-off” days. As part of routine clinical 
care, it is also not uncommon to adjust days on and off to help address variable 
tolerance of the device use for patients with these implants. Patients also in the 
course of their clinical care may opt to turn the device off on some nights (such as 
for comfort) as part of their routine clinical care.  
The Investigators have weighed the adequacy of protection against the importance of 
knowledge gained and determined the risks to be justified. Whether sleep disruption can 
truly result in any given AF event remains unknown—in fact whether AF can be triggered 
by any modifiable exposure has not yet been proven in a randomized trial. The importance 
of the knowledge to be gained from this study is therefore two-pronged: first, the acute 
effects of sleep disruptions are relevant to the third of the US population who have 
insufficient sleep. Second, understanding the mechanism that results in the initiation of 
AF episodes, or the development of incident AF is relevant to the rapidly growing and 
large number of AF patients because it will reveal mechanisms germane to AF itself. All 
taken together, the minimal risks incurred by study participants are reasonable considering 
the broadly applicable knowledge to be gained.  
 
9 
DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS 
9.1 
Early Discontinuation from Randomization  
A participant may be discontinued from randomization at any time if the participant or the 
investigator feels that it is not in the participant’s best interest to continue. The following 
is a list of possible reasons for study treatment discontinuation:  
• Participant withdrawal of consent 

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• Adverse event that in the opinion of the investigator would be in the best interest 
of the participant to discontinue treatment 
• Lost to follow-up 
• Early termination of the study (<2 days) 
• Positive pregnancy test 
All participants are free to withdraw from participation at any time, for any reason, 
specified or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for 
participant withdrawals. The reason for the participant’s withdrawal from the study will be 
specified in the participant’s source documents. 
9.2 
Withdrawal of Participants from the Study 
A participant may be withdrawn from the study at any time if the participant or the 
investigator feels that it is not in the participant’s best interest to continue.   
All participants are free to withdraw from participation at any time, for any reason, 
specified or unspecified, and without prejudice. 
9.3 
Replacement of Participants 
Participants who withdraw from the study will be replaced.   
 
10 STATISTICAL METHODS AND CONSIDERATIONS 
10.1 Sample Size and Randomization 
Based on the frequencies that cardiac ectopy observed among 100 healthy individuals 
during a study examining acute effects on and off coffee, we estimate that, using a two-
tailed alpha of 0.05, we will have 80% power in intention-to-treat analyses comparing 
nights on and off HGNS to detect a 2% increase in cardiac ectopy—meaning, we believe 
100 participants will provide adequate power to test our hypothesis.   
10.2 Statistical Analysis Plan (SAP) and Outcome Assessment 
Our primary analyses will employ intention-to-treat principles, examining randomization 
assignment as the primary predictor. Secondary analyses will examine “per-protocol” 
compliance, which will also allow for quantitative assessments of outcomes per the 
number of hours off hypoglossal stimulation as the predictor. We will employ logistic 
regression with robust standard errors (to take clustering within individuals into account) 
for the dichotomous presence or absence of outcomes (such as at least one daily PAC, 
PVC, or episode of AF), and a negative binomial model to assess number of daily events. 
10.3 Intention-to-Treat (ITT) 
The main intention-to-treat (ITT) analysis set will include all randomized participants, 
whether they are compliant with the treatment allocation for this trial or not. Every 

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attempt will be made to collect data until the end of the follow-up period for all 
randomized participants and these data will be included as part of the main ITT analysis. 
The analyses for the primary objective will be performed using the ITT dataset. 
Although substantial crossover is not anticipated, as treated analyses will also be 
conducted if failure to comply with allocated treatment assignments occurs in more than 
10% of cases or if there is a significantly different proportion of assignment adherence for 
“ON” versus “OFF” HGNS use. 
 
11 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312). 
11.1 Protocol Amendments 
Protocol amendments cannot be implemented without prior written IRB/IEC approval 
except as necessary to eliminate immediate safety hazards to patients. A protocol 
amendment intended to eliminate an apparent immediate hazard to patients may be 
implemented immediately, provided the IRBs are notified within five working days. 
11.2 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, 
International Conference on Harmonization Good Clinical Practice, US Code of Federal 
Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, and CFR 
Part 56, Subpart A), the Health Insurance Portability and Accountability Act (if 
applicable), and local regulations. 
The consent form generated by the Investigator must be approved by the IRB/IEC. 
The written consent document will embody the elements of informed consent as described 
in the International Conference on Harmonisation and will also comply with local 
regulations.  
A properly executed, written, informed consent will be obtained from each participant 
prior to entering the participant into the trial. 
 
12 REFERENCES 
1. 
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VanWagner LB, Wang NY and Tsao CW. Heart Disease and Stroke Statistics-2021 
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Fitzmaurice C, Naghavi M, Sadat N, Shieh P, Squires E, Yeung K and Murray CJL. US 
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Christensen MA, Dixit S, Dewland TA, Whitman IR, Nah G, Vittinghoff E, 
Mukamal KJ, Redline S, Robbins JA, Newman AB, Patel SR, Magnani JW, Psaty BM, 
Olgin JE, Pletcher MJ, Heckbert SR and Marcus GM. Sleep characteristics that predict 
atrial fibrillation. Heart Rhythm. 2018;15:1289-1295. 
5. 
Genuardi MV, Ogilvie RP, Saand AR, DeSensi RS, Saul MI, Magnani JW and 
Patel SR. Association of Short Sleep Duration and Atrial Fibrillation. Chest. 
2019;156:544-552. 
6. 
Mitchell AR, Spurrell PA and Sulke N. Circadian variation of arrhythmia onset 
patterns in patients with persistent atrial fibrillation. Am Heart J. 2003;146:902-7. 
7. 
Deguchi Y, Amino M, Adachi K, Matsuzaki A, Iwata O, Yoshioka K, Watanabe E 
and Tanabe T. Circadian distribution of paroxysmal atrial fibrillation in patients with and 
without structural heart disease in untreated state. Ann Noninvasive Electrocardiol. 
2009;14:280-9. 
8. 
Groh CA, Faulkner M, Getabecha S, Taffe V, Nah G, Sigona K, McCall D, Hills 
MT, Sciarappa K, Pletcher MJ, Olgin JE and Marcus GM. Patient-reported triggers of 
paroxysmal atrial fibrillation. Heart Rhythm. 2019;16:996-1002. 
9. 
Wong CX, Modrow MF, Sigona K, Tang JJ, Vittinghoff E, Hills MT, McCall D, 
Sciarappa K, Pletcher MJ, Olgin JE and Marcus GM. Preceding Night Sleep Quality and 
Atrial Fibrillation Episodes in the I-STOP-AFIB Randomized Trial. JACC Clin 
Electrophysiol. 2024;10:56-64. 
10. 
Marcus GM, Modrow MF, Schmid CH, Sigona K, Nah G, Yang J, Chu TC, Joyce 
S, Gettabecha S, Ogomori K, Yang V, Butcher X, Hills MT, McCall D, Sciarappa K, Sim 
I, Pletcher MJ and Olgin JE. Individualized Studies of Triggers of Paroxysmal Atrial 
Fibrillation: The I-STOP-AFib Randomized Clinical Trial. JAMA Cardiol. 2022;7:167-
174. 
11. 
Benjamin EJ, Al-Khatib SM, Desvigne-Nickens P, Alonso A, Djoussé L, Forman 
DE, Gillis AM, Hendriks JML, Hills MT, Kirchhof P, Link MS, Marcus GM, Mehra R, 
Murray KT, Parkash R, Piña IL, Redline S, Rienstra M, Sanders P, Somers VK, Van 
Wagoner DR, Wang PJ, Cooper LS and Go AS. Research Priorities in the Secondary 
Prevention of Atrial Fibrillation: A National Heart, Lung, and Blood Institute Virtual 
Workshop Report. J Am Heart Assoc. 2021;10:e021566. 
12. 
Gray JR. A Bias Toward Short-Term Thinking in Threat-Related Negative 
Emotional States. Personality and Social Psychology Bulletin. 1999;25:65-75. 

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13. 
Fischer AG, Bourgeois-Gironde S and Ullsperger M. Short-term reward 
experience biases inference despite dissociable neural correlates. Nat Commun. 
2017;8:1690. 
14. 
Traaen GM, Aakerøy L, Hunt TE, Øverland B, Bendz C, Sande L, Aakhus S, 
Fagerland MW, Steinshamn S, Anfinsen OG, Massey RJ, Broch K, Ueland T, Akre H, 
Loennechen JP and Gullestad L. Effect of Continuous Positive Airway Pressure on 
Arrhythmia in Atrial Fibrillation and Sleep Apnea: A Randomized Controlled Trial. Am J 
Respir Crit Care Med. 2021;204:573-582. 
15. 
Hunt TE, Traaen GM, Aakerøy L, Bendz C, Øverland B, Akre H, Steinshamn S, 
Loennechen JP, Hegbom F, Broch K, Lie Ø H, Lyseggen E, Haugaa KH, Gullestad L and 
Anfinsen OG. Effect of continuous positive airway pressure therapy on recurrence of 
atrial fibrillation after pulmonary vein isolation in patients with obstructive sleep apnea: A 
randomized controlled trial. Heart Rhythm. 2022;19:1433-1441. 
16. 
Dewland TA, Vittinghoff E, Mandyam MC, Heckbert SR, Siscovick DS, Stein 
PK, Psaty BM, Sotoodehnia N, Gottdiener JS and Marcus GM. Atrial ectopy as a 
predictor of incident atrial fibrillation: a cohort study. Ann Intern Med. 2013;159:721-8. 
17. 
Howell SJ, Dukes JW, Vittinghoff E, Tang JJ, Moss JD, Lee RJ, Lee BK, Tseng 
ZH, Vedantham V, Olgin JE, Scheinman MM, Hsia H, Gerstenfeld EP and Marcus GM. 
Premature Atrial Contraction Location and Atrial Fibrillation Inducibility. Circ Arrhythm 
Electrophysiol. 2023;16:e011623. 
18. 
Farinha JM, Gupta D and Lip GYH. Frequent premature atrial contractions as a 
signalling marker of atrial cardiomyopathy, incident atrial fibrillation, and stroke. 
Cardiovasc Res. 2023;119:429-439. 
19. 
Dukes JW, Dewland TA, Vittinghoff E, Mandyam MC, Heckbert SR, Siscovick 
DS, Stein PK, Psaty BM, Sotoodehnia N, Gottdiener JS and Marcus GM. Ventricular 
Ectopy as a Predictor of Heart Failure and Death. J Am Coll Cardiol. 2015;66:101-9. 
20. 
Marcus GM. Evaluation and Management of Premature Ventricular Complexes. 
Circulation. 2020;141:1404-1418. 
21. 
Marcus GM, Rosenthal DG, Nah G, Vittinghoff E, Fang C, Ogomori K, Joyce S, 
Yilmaz D, Yang V, Kessedjian T, Wilson E, Yang M, Chang K, Wall G and Olgin JE. 
Acute Effects of Coffee Consumption on Health among Ambulatory Adults. N Engl J 
Med. 2023;388:1092-1100. 
22. 
Marcus GM, Vittinghoff E, Whitman IR, Joyce S, Yang V, Nah G, Gerstenfeld 
EP, Moss JD, Lee RJ, Lee BK, Tseng ZH, Vedantham V, Olgin JE, Scheinman MM, Hsia 
H, Gladstone R, Fan S, Lee E, Fang C, Ogomori K, Fatch R and Hahn JA. Acute 
Consumption of Alcohol and Discrete Atrial Fibrillation Events. Ann Intern Med. 
2021;174:1503-1509. 
23. 
Strollo PJ, Jr., Soose RJ, Maurer JT, de Vries N, Cornelius J, Froymovich O, 
Hanson RD, Padhya TA, Steward DL, Gillespie MB, Woodson BT, Van de Heyning PH, 
Goetting MG, Vanderveken OM, Feldman N, Knaack L and Strohl KP. Upper-airway 
stimulation for obstructive sleep apnea. N Engl J Med. 2014;370:139-49. 
24. 
Schwartz AR, Jacobowitz O, Eisele DW, Mickelson SA, Miller MB, Oliven A, 
Certal V, Hopp ML, Winslow DH, Huntley TC, Nachlas NE, Pham LV, Gillespie MB, 
Weeks BH, Lovett EG, Shen J, Malhotra A and Maurer JT. Targeted Hypoglossal Nerve 

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Stimulation for Patients With Obstructive Sleep Apnea: A Randomized Clinical Trial. 
JAMA Otolaryngol Head Neck Surg. 2023;149:512-520. 
25. 
Yalamanchali S, Farajian V, Hamilton C, Pott TR, Samuelson CG and Friedman 
M. Diagnosis of obstructive sleep apnea by peripheral arterial tonometry: meta-analysis. 
JAMA Otolaryngol Head Neck Surg. 2013;139:1343-50. 
26. 
Woodson BT, Gillespie MB, Soose RJ, Maurer JT, de Vries N, Steward DL, 
Baskin JZ, Padhya TA, Lin HS, Mickelson S, Badr SM, Strohl KP and Strollo PJ, Jr. 
Randomized controlled withdrawal study of upper airway stimulation on OSA: short- and 
long-term effect. Otolaryngol Head Neck Surg. 2014;151:880-7. 
 

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Protocol Template © CFFT TDN   Effective: 12 SEP 2007 
APPENDIX 1.  SCHEDULE OF EVENTS 
 
PRE-SCREENING 
(Pre-Consent) 
BASELINE VISIT 
(Before Day 1) 
DEVICE FITTING 
VISIT 
(Day 1) 
MONITORING 
(Day 1-15b) 
MONITORING 
CLOSE-OUT VISIT 
(Day 15b) 
Eligibility Review 
X 
 
 
 
 
Informed Consent 
 
X 
 
 
 
Demographics 
 
X 
 
 
 
Medical Conditions 
 
X 
 
 
 
Medications 
 
X 
 
 
 
Baseline Alcohol Consumption  
 
X 
 
 
 
Smoking History 
 
X 
 
 
 
Arrhythmia History  
 
X 
 
 
 
Baseline sleep surveys 
 
X 
 
 
 
Mobile apps download and set up 
 
 
X 
 
 
ECG monitor application 
 
 
X 
 
 
Randomization 
 
 
 
X 
 
Daily sleep surveys 
 
 
 
X 
 
Home Sleep Apnea Test 
 
 
 
X 
 
Monitor return 
 
 
 
 
X 
Randomization Compliance Survey 
 
 
 
 
X 
a These activities will only be completed if a participant is willing and able (and are therefore considered “optional”) 
b 15 days or for as long as a participant is tolerant of study monitors (whichever occurs first)