A Pilot Study to Evaluate the Safety and Efficacy of the Hypoglossal Nerve Stimulator in Adolescents and Young Adults With Down Syndrome and Obstructive Sleep Apnea
Phase: NA
Conditions: Sleep Apnea, Obstructive, Down Syndrome
Sponsor: Christopher Hartnick, M.D.

A PILOT STUDY TO EVALUATE SAFETY AND 
EFFICACY OF THE HYPOGLOSSAL NERVE 
STIMULATOR IN ADOLESCENTS WITH DOWN 
SYNDROME AND OBSTRUCTIVE SLEEP APNEA 
 
Protocol Number: 14-146H 
Sponsor-Investigator: Christopher Hartnick, MD 
Funded By: Inspire Medical Systems 
 
Device: Inspire Upper Airway system 
IDE: G140209 
Device has prior FDA approval (PMA and IDE P130008, G080122) 
NCT 02344108 
 
Version Number:  v.9.5; 08 May 2020 
 
Document History Summary  
Version # 
Version Date 
9.5 
08 May 2020 
9.0 
05 Jul 2019 
8.0 
29 Mar 2018 
1.0 – 7.0 
2014 – 2018 
 
 
 
 

 
 
Pediatric HGN Study 
 
 
Protocol: 14-146H 
v. 9.5; 08 May 2020 
 
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Table of Contents  
Acronyms & Abbreviations............................................................................................................................................... 5 
Schema .................................................................................................................................................................................. 6 
Protocol Summary .............................................................................................................................................................. 7 
Principal Investigator Signature Page .............................................................................................................................. 9 
1 
Introduction ............................................................................................................................................................. 10 
1.1 
Study Rationale ............................................................................................................................................... 10 
1.2 
Background ...................................................................................................................................................... 10 
2 
Objectives ................................................................................................................................................................. 11 
2.1 
Primary Objectives ......................................................................................................................................... 11 
2.2 
Secondary Objectives ..................................................................................................................................... 11 
3 
Study Design ............................................................................................................................................................ 11 
4 
Patient Selection ...................................................................................................................................................... 11 
4.1 
Inclusion Criteria ............................................................................................................................................ 11 
4.2 
Exclusion Criteria ........................................................................................................................................... 12 
4.3 
Strategies for Recruitment and Retention................................................................................................... 12 
5 
Study Procedures .................................................................................................................................................... 13 
5.1 
Schedule of Events ......................................................................................................................................... 13 
5.2 
Assessments ..................................................................................................................................................... 13 
5.2.1 
Physical Exam with Functional Tongue Exam ................................................................................ 13 
5.2.2 
Surgical Consultation ............................................................................................................................ 14 
5.2.3 
Quality of Life Questionnaires ............................................................................................................ 14 
5.2.4 
In-Lab Titration Sleep Study: Polysymnography (PSG) ................................................................. 14 
5.2.5 
Drug Induced Sleep Endoscopy (DISE) ........................................................................................... 15 
5.2.6 
Device Check ......................................................................................................................................... 15 
5.3 
Study Visits ...................................................................................................................................................... 16 
5.3.1 
Screening / Baseline .............................................................................................................................. 16 
5.3.2 
Surgery ..................................................................................................................................................... 16 
5.3.3 
Device Activation and Initial Titration .............................................................................................. 17 
5.3.4 
Follow-up Study Visits ......................................................................................................................... 17 
5.3.5 
Unscheduled Visits ................................................................................................................................ 17 
5.4 
Concomitant Medications and Procedures ................................................................................................ 18 
5.5 
Participant Discontinuation / Withdrawal from the Study ..................................................................... 18 
5.5.1 
Discontinuation of Device ................................................................................................................... 18 
5.5.2 
Participant Withdrawal from the Study ............................................................................................. 18 
5.5.3 
Device Failure, Revision, and Explant ............................................................................................... 18 
5.5.4 
Participant Lost to Follow-up ............................................................................................................. 19 

 
 
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6 
Study Device ............................................................................................................................................................ 20 
6.1 
Device Components....................................................................................................................................... 20 
6.1.1 
Implantable Pulse Generator (IPG) ................................................................................................... 20 
6.2 
Acquisition and accountability...................................................................................................................... 22 
6.3 
Product Storage and Stability ........................................................................................................................ 22 
6.3.1 
IPG .......................................................................................................................................................... 22 
6.3.2 
Leads ........................................................................................................................................................ 22 
7 
Risks and Benefits ................................................................................................................................................... 23 
7.1 
Known Potential Risks .................................................................................................................................. 23 
7.1.1 
Risks of Screening Procedures ............................................................................................................ 23 
7.1.2 
Risk of Implantation Surgery ............................................................................................................... 23 
7.1.3 
Pregnancy Risks ..................................................................................................................................... 25 
7.1.4 
Psychosocial (non-medical) Risks ....................................................................................................... 25 
7.1.5 
Considerations for Future Medical Care ........................................................................................... 25 
7.2 
Known Potential Benefits ............................................................................................................................. 26 
8 
Data Safety and Monitoring .................................................................................................................................. 26 
8.1 
Data Safety and Monitoring Board .............................................................................................................. 26 
8.2 
Research monitor ............................................................................................................................................ 26 
8.3 
Regular Site Monitoring ................................................................................................................................. 26 
8.4 
Adverse Event Monitoring and Reporting ................................................................................................. 27 
8.4.1 
AE Definitions for Investigator Classification ................................................................................. 27 
8.4.2 
Adverse Event Reporting ..................................................................................................................... 28 
8.4.3 
Anticipated Adverse Device-Related Events .................................................................................... 29 
8.4.4 
Technical Observation/Device Deficiencies .................................................................................... 29 
8.4.5 
Subject Death ......................................................................................................................................... 30 
9 
Statistical Considerations ....................................................................................................................................... 30 
9.1 
Primary endpoint(s) or outcome measure(s) .............................................................................................. 30 
9.2 
Secondary endpoints or outcome measure(s) ............................................................................................ 30 
9.3 
Sample Size Determination ........................................................................................................................... 31 
9.4 
Analysis Population ........................................................................................................................................ 31 
9.5 
Effectiveness Analysis (if applicable) .......................................................................................................... 31 
9.6 
Safety Analysis ................................................................................................................................................. 31 
10 
Ethical Considerations ........................................................................................................................................... 31 
10.1 
Review by an Institutional Review Board ................................................................................................... 31 
10.2 
Informed Consent .......................................................................................................................................... 31 
10.2.1 
Inclusion of Minors ............................................................................................................................... 31 
10.2.2 
Inclusion of Persons not Competent to Consent ............................................................................ 32 

 
 
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10.2.3 
Non-English Speaking Subjects .......................................................................................................... 32 
10.3 
Statement of Compliance .............................................................................................................................. 32 
References .......................................................................................................................................................................... 32 
 
 

 
 
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Acronyms & Abbreviations 
Term 
Meaning 
AE 
Adverse Event 
AHI 
Apnea/Hypopnea Index 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CMP 
Clinical Monitoring Plan 
CRF 
Case Report Form 
DHHS 
Department of Health and Human Services 
DISE 
Drug Induced Sleep Endoscopy 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Forms 
ESS 
Epworth Sleepiness Scale 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization  
IDE 
Investigational Device Exemption 
IPG 
Implantable Pulse Generator 
IRB 
Institutional Review Board 
MEEI 
Massachusetts Eye and Ear 
MOP 
Manual of Procedures 
OHRP 
Office for Human Research Protections 
OSA 
Obstructive Sleep Apnea 
OSA-18 Obstructive Sleep Apnea-18 Questionnaire 
PI 
Principal Investigator 
PSG 
Polysomnograpy 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
 
 
 

 
 
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Schema 
 
 
 

 
 
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Protocol: 14-146H 
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Protocol Summary 
Title:  
A pilot study to evaluate safety and efficacy of the hypoglossal nerve 
stimulator in adolescents with Down syndrome and obstructive sleep apnea 
Investigational Device:  
Inspire® Upper Airway Simulation System, Model 3028 IPG (previously 
Model 3024 IPG) 
Study Design:  
This is a multicenter, prospective, single-arm study of an implantable device 
for the treatment of obstructive sleep apnea in patients with Down 
syndrome and previous treatment of adenotonsillectomy.  
Accrual Goal:  
Up to 42 
Patient Population:  
Subjects aged 10-21 with Down syndrome and Obstructive Sleep Apnea 
with previous treatment of adenotonsillectomy.  
Inclusion 
/ 
Exclusion 
Criteria:  
Inclusion Criteria:  
All subjects that participate in this study must meet the following 
criteria:  
1. Children and young adults with Down syndrome 
2. Age 10-21 years  
3. Prior adenotonsillectomy 
4. Moderate to severe OSA (AHI >10, AHI <50, no more than 25% 
AHI attributable to central events) based on prior in-lab PSG 
performed after adenotonsillectomy 
5. Subjects must have either tracheotomy or be ineffectively treated 
with CPAP due to noncompliance, discomfort, un-desirable side 
effects, persistent symptoms despite compliance use, or refusal to 
use the device. 
6. Children and their parents must be willing to have stimulation 
hardware permanently implanted, and be willing to participate in 
follow-up visits, postoperative PSG, and questionnaire completion. 
7. Children’s parents must complete a questionnaire confirming that 
their child is capable of communicating feelings of pain or 
discomfort.  They must also confirm they are able to assess their 
child for adverse effects related to device implantation.   
8. Children and their parents must be proficient in English. 
Exclusion Criteria:  
The presence of any of the following will exclude a potential subject 
from participation:  
1. BMI>the 95th percentile for age  
2. Any anatomic finding on physical exam or DISE that would 
compromise the performance of stimulation (e.g. concentric soft 
palate collapse) 
3. Other medical conditions resulting in medical instability (e.g. 
congestive 
heart 
failure, 
recent 
open 
heart 
surgery, 
immunosuppression, or chronic lung disease or aspiration)  
4. Presence of another medical condition requiring future magnetic 
resonance imaging (MRI) of the chest 
5. Patients with another implantable device which could interact 
unintentionally with the Inspire system 
6. Any contraindication for general anesthesia 
7. Life expectancy < 12 months 
8. Inability 
to 
communicate 
pain 
or 
discomfort 
to 
their 
caretaker/parent, based on parental or investigator assessment 
9. History of bleeding or clotting disorders and those on blood 

 
 
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thinning or NSAID medications for the week prior implantation 
surgery.  Subjects will be asked to refrain from the use of NSAIDS 
for two weeks after the implantation or any revision surgeries. 
10. Taking muscle relaxant medication 
11. Female subjects who are pregnant or plan to become pregnant 
during the study period.  
12. Subjects deemed unfit for participation by investigators or any 
other reason. 
Objectives: 
Primary Objectives:  
1. Evaluate device related serious adverse events from implant to 12 
month follow-up 
2. Evaluate device-related adverse events from implant to 12 month 
follow-up 
Secondary Objectives:  
1. Therapy efficacy measured by OSA-18 and ESS at 12 month 
follow-up  
2. Therapy efficacy measured by AHI at 12 month follow-up 
3. Objective mean weekly usage data obtained from the physician 
programmer at the 12 month visit 
Investigational 
Intervention:  
All enrolled patients will undergo device implantation surgery of the 
investigational device, device activation, and several follow-up visits.  
 
 
 

 
 
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Principal Investigator Signature Page 
 
Protocol Title: A pilot study to evaluate safety and efficacy of the hypoglossal nerve stimulator in 
adolescents with Down syndrome and obstructive sleep apnea  
 
Protocol #: 14-146H 
 
Protocol Version Number/Date: Version 9.0; 05 July 2019 
 
I, the undersigned, have read and understood the protocol specified above and agree on its content. I agree to 
perform and conduct the study as described in the protocol and in accordance with the relevant 
laws/regulations and standards outlined in the Clinical Trial Agreement. 
 
 
 
_______________________________________________________ 
Name 
 
 
 
_______________________________________________________ 
Signature 
 
 
 
_____________________________ 
Date 
 
 

 
 
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1 
Introduction 
1.1 
Study Rationale 
Obstructive sleep apnea (OSA) affects up to 1% of the general pediatric population and is associated with 
adverse behavior and quality of life, as well as long term cardiopulmonary system complications.  Trisomy 21 
(Down syndrome) is the most common chromosomal disorder, with an incidence of approximately 1 per 
660-800 births. Patients with Down syndrome have a higher incidence of OSA than the general pediatric 
population, with rates of 30-60%, resulting in increased morbidity and decreased quality of life for affected 
individuals.  In children, adenotonsillar hypertropy is often a contributing factor to OSA, and 
adenotonsillectomy is a first line treatment.  Children with Down syndrome often undergo T&A for 
obstructive sleep apnea; however 30-50% will have persistent obstructive sleep patterns requiring continuous 
positive pressure airway support (CPAP) or tracheotomy. Persistent obstruction is attributed to anatomic and 
physiologic differences in this population, including reduced muscular tone, macroglossia, maxillary 
hypoplasia, and lingual tonsil hypertrophy.  This pilot study is designed to determine if the Inspire® Upper 
Airway Simulation System, Model 3024 IPG (now Model 3028 IPG; see below), which has already been 
approved for use in adults with OSA, can be safely implanted and used in the treatment of adolescents and 
young adults with Down Syndrome.  
 
The Inspire system was developed to treat moderate to severe OSA (15 ≤ Apnea Hypopnea - AHI ≤ 65) in 
adult patients who are not effectively treated by CPAP. The Inspire system is comprised of the following 
components: 
 
Inspire II Upper Airway Stimulator, Model 3024 (Implantable Pulse Generator, IPG) and any 
subsequent iteration thereof that are approved under P130008 for the treatment of obstructive sleep apnea which are 
listed below and updated as needed via protocol modifications submitted to the FDA.  Note: Inspire Model 3028 
IPG received FDA approval on May 5, 2017 and replaces Model 3024 IPG. 
 
Inspire Stimulation Lead, Model 4063 (stimulation lead) 
 
Inspire Sensing Lead, Model 4323 (sensing lead) 
 
External programmers used with the system are: 
o Inspire Programmer, Model 2740 (physician programmer) 
o Inspire Patient Programmer, Model 3032 (patient programmer) 
1.2 
Background 
A global pivotal trial (the STAR trial) and three feasibility studies have been performed with the Inspire 
system.  The first feasibility study (Inspire 1) implanted the Inspire I system in 8 subjects demonstrating the 
feasibility and safety of the approach.   
 
Two additional feasibility clinical studies using the second generation Inspire system have verified the 
reliability of system components, and identified the specific inclusion and exclusion criteria in order for 
patients to obtain the maximum benefits from the Inspire system.   
 
The STAR phase III pivotal trial demonstrated the safety, efficacy, and usability of the Inspire system.  The 
study was conducted at 15 investigational sites in the United States and 7 investigational sites in Europe.  The 
study followed 126 subjects implanted with the Inspire system.  The study results met and exceeded all 
primary and secondary endpoints.  Inspire therapy demonstrated statistically significant reduction of OSA 
severity, clinically meaningful improvement of quality of life, and with a safety profile well accepted by study 
subjects. 
 
This protocol is the first known trial of children with Down syndrome being implanted with the Inspire 
system.  Preliminary results were published for the first patient (1), the first 6 patients (2), and later for the 
first 20 implanted patients (3).  

 
 
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2 Objectives 
2.1 
Primary Objectives 
1. Evaluate device-related serious adverse events from implant to 12 month follow-up 
2. Evaluate device-related adverse events from implant to 12 month follow-up 
 
2.2 Secondary Objectives 
1. Efficacy of HGN stimulation as measured by OSA-18 and ESS at 12 month follow up 
2. Efficacy of HGN stimulation as measured by AHI at 12 month follow-up 
3. Objective mean weekly usage data obtained from the physician programmer at 12 month follow-up 
 
3 Study Design 
The study is a multi-center, prospective, single-arm study conducted under a common implant and follow-up 
protocol.  Fifty adolescents and young adults (10-21 years of age) with Down syndrome with moderate to 
severe obstructive sleep apnea after adenotonsillectomy.  
 
After providing informed consent, patients (with input from their parents/guardians as appropriate) will be 
screened according to the eligibility criteria below.  Subjects will then undergo preoperative evaluation with an 
in-lab polysomnogram (PSG) (if available, an in-lab PSG performed within 18 months prior to study 
consent may be used), evaluation by a pediatric otolaryngology surgeon, and drug induced sleep endoscopy 
(DISE) (If available, a DISE that was performed within 18 months of the study consent may be used) 
to ensure all inclusion and exclusion criteria are met.   
 
Subjects meeting eligibility criteria will then undergo hypoglossal nerve implantation of the Inspire® Upper 
Airway Simulation System. Surgery will be performed by pediatric otolaryngologists who have completed a 
training program for the Inspire system.   
 
Subjects will then adhere to a follow-up schedule.  The device will be activated and settings titrated during an 
in-lab sleep study 1 month postoperatively.  Quality of life surveys and device interrogation will be conducted 
at timed intervals.  Subjects will then undergo in-lab polysomnography at 2 months, 6 months, and 12-
months, and the device titrated as needed.  All personnel adjusting device parameters will be trained in 
programming the Inspire system. For this pilot study, we will evaluate safety and efficacy over the first year 
after device implantation. 
4 Patient Selection 
4.1 
Inclusion Criteria 
All subjects that participate in this study must meet the following criteria:  
1. Children and young adults with Down syndrome 
2. Age 10-21 years  
3. Prior adenotonsillectomy 
4. Moderate to severe OSA (AHI >10, AHI <50, no more than 25% AHI attributable to central 
events) based on prior in-lab polysomnography performed after adenotonsillectomy 
5. Subjects must have either tracheotomy or be ineffectively treated with CPAP due to noncompliance, 
discomfort, un-desirable side effects, persistent symptoms despite compliance use, or refusal to use 
the device. 

 
 
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6. Children and their parents must be willing to have stimulation hardware permanently implanted, and 
be willing to participate in follow-up visits, postoperative polysomnography, and questionnaire 
completion. 
7. Children’s parents must complete a questionnaire confirming that their child is capable of 
communicating feelings of pain or discomfort.  They must also confirm they are able to assess their 
child for adverse effects related to device implantation.   
8. Children and their parents must be proficient in English for this pilot study in order to ensure full 
disclosure during the consent process, as well as have the ability to communicate with all staff, at all 
times, regarding any questions about participation or concerns about this device.  In further studies, 
we plan to expand study materials and resources in order to include patients who are non-English 
speaking. Given the small scale of this pilot study, we feel initial exclusion of non-English speaking 
individuals should not adversely affect applicability of our results to the general population, nor 
should it prevent all qualified patients from eventual access to device implantation. 
 
4.2 Exclusion Criteria 
The presence of any of the following will exclude a potential subject from participation:  
1. BMI>the 95th percentile for age  
2. Any anatomic finding on physical exam or drug induced sleep endoscopy (DISE) that would 
compromise the performance of stimulation (e.g. concentric soft palate collapse),  
3. Other medical conditions resulting in medical instability (e.g. congestive heart failure, recent open 
heart surgery, immunosuppression, or chronic lung disease or aspiration)  
4. Presence of another medical condition requiring future magnetic resonance imaging (MRI) of the 
chest 
5. Patients with another implantable device which could interact unintentionally with the Inspire system 
6. Any contraindication for general anesthesia 
7. Life expectancy < 12 months 
8. Inability to communicate pain or discomfort to their caretaker/parent, based on parental or 
investigator assessment 
9. History of bleeding or clotting disorders and those on blood thinning or NSAID medications for the 
week prior implantation surgery.  Subjects will be asked to refrain from the use of NSAIDS for two 
weeks after the implantation or any revision surgeries. 
10. Taking muscle relaxant medication 
11. Female subjects who are pregnant or plan to become pregnant during the study period.  All female 
subjects aged 11 and up will undergo urine beta-HCG testing on the day of procedures requiring 
general anesthesia (DISE, implantation, and any other unanticipated surgical procedures related to 
implantation).  Subjects who are positive will not undergo surgical implantation or procedures under 
general anesthesia. 
12. Subjects deemed unfit for participation by investigators or any other reason. 
 
4.3 Strategies for Recruitment and Retention  
Up to forty-two (42) subjects will be recruited from the practices of participating investigators as well as 
referrals to these investigators; however, the study may stop after enrollment of only 40 subjects if some 
participants choose not to undergo surgery. Subjects who are deemed appropriate for the study (e.g. by 
answering screening questions and meeting general study criteria such as age) during their initial contact with 
the site investigator will be approached to participate and given information about the study by the site 
investigator and study staff. Subjects will be given the opportunity to ask any questions and if desired, the 
consent forms so they can review the study away from study staff. Subjects will also be given contact 
information for the study team should they have further questions once they leave the clinic or hospital.   
 

 
 
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Furthermore, if enrollment for a particular group does not seem adequate, then steps will be taken to 
promote increased enrollment of the under-represented group. Such steps include: 1) we will contact regional 
pediatric ENT clinics and post information in clinics that specifies that female or minority children with DS 
are especially desired; 2); we will reach out to local, state, regional, and national Down syndrome groups, and 
3) an additional study site may be added. 
5 Study Procedures 
5.1 
Schedule of Events 
 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
 
Screening 
/ Baseline 
Implant 
Surgery 
Device 
Activation 
(1M post-op) 
2M (5) 
6M (5) 
12M (5) 
Eligibility 
X 
 
 
 
 
 
Informed Consent  
X (1) 
X (2) 
 
 
 
 
Surgical Consultation  
X 
 
 
 
 
 
Limited Physical Exam 
X 
 
X 
X 
X 
X 
Functional Tongue Exam 
X 
X 
X 
X 
X 
X 
Medication Reconciliation 
X 
 
X 
X 
X 
X 
QOL (ESS, OSA-18) 
X 
 
 
 
 
X 
In-Lab PSG 
X (3) 
 
X 
X 
X 
X 
DISE 
X (3) 
 
 
 
 
 
Urine Pregnancy 
X (6) 
 
 
 
 
 
Surgery 
 
X 
 
 
 
 
Device Check 
 
 
X 
X 
X 
X 
AE Review  
 
X 
X 
X 
X 
X 
(1) Informed Consent may be done in 2 stages if approved by the institution’s local IRB.  For patients 
who are considering participation but do not have the funds to travel to the study site for pre-
screening, a remote consent may be conducted (if IRB approved) to allow for review of medical 
records for the purpose of screening for the study. Stage 2 will be in person consent for participation 
in the study.  In person consent for participation in the study is required for all subjects. 
(2) Separate surgical consent is obtained as part of standard of care based on institutional requirements.  
(3) If In-lab PSG and DISE done as part of standard of care within 18 months of consent, these tests do 
not need to be repeated.  
(4) 4-14 days post activation 
(5) +/- 30 days  
(6) Done for females age 11 and up prior to procedures done on study that require anesthesia 
 
5.2 Assessments 
5.2.1 
Limited Physical Exam with Functional Tongue Exam 
A limited physical examination will occur for each subject during study visit. This examination will be 
performed at Baseline, 1-, 2-, 6- and 12-month follow-ups. 
 
At the Baseline visit, the examination will ensure that the subject is a good candidate to continue in the trial 
and receive the intended therapy.  If any tongue dysfunction, atrophy, hypertrophy, fasciculations, problems 
swallowing or speaking are noted during the exam, they will be recorded. 
 
At the post-implant follow-up visits, the exam will assess: appearance of surgical wound at the neck, facial 
nerve function, appearance of surgical wound on the chest, and tongue function. The tongue function exam 

 
 
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will assess any variation from the Baseline observations. Furthermore, the tongue exam is intended to detect 
any temporary or permanent damage to the hypoglossal nerve.  For this reason, special attention is paid to 
muscle atrophy or hypertrophy, fasciculations, or limitations in tongue motion. 
 
5.2.2 
Surgical Consultation  
Subjects will undergo a surgical consultation during pre-implant screening. The surgeon will perform a 
thorough head and neck examination, including laryngoscopy to evaluate the entire upper airway.  A digital 
picture of the tongue and soft palate region may be taken (optional).   
 
The subject will be disqualified for implant if any pronounced anatomical abnormalities exist (e.g., tonsil size 
of 3 or 4) that, in the Investigator’s opinion, prevent effective use or assessment of the Inspire therapy.  If a 
subject is excluded on the basis of Investigator opinion, the specific reason for exclusion will be documented. 
 
5.2.3 
Quality of Life Questionnaires 
5.2.3.1 
Epworth Sleepiness Scale (ESS) 
The Epworth Sleepiness Scale (ESS) is a validated, self-report instrument that rates a subject’s tendency to fall 
asleep in eight common daily situations (4).  The ESS Scale has been validated primarily in OSA.  It is used to 
measure excessive daytime sleepiness, and is often utilized before and after the administration of treatment to 
document improvement of symptoms.   
 
The ESS will be completed during the Baseline visit and 12-month follow-up. 
5.2.3.2 
Obstructive Sleep Apnea-18 (OSA-18) 
The Obstructive Sleep Apnea-18 (OSA-18) is a survey given to caregivers to assess how sleep disordered 
breathing effects on the daily life of their children. It contains 18 questions related to 5 domains: 1) sleep 
disturbance, 2) physical suffering, 3) emotional distress, 4) day time problems, and 5) caregiver concerns. The 
survey has been shown to have good reliability and validity. The survey takes 5 to 10 minutes to complete.  
 
A change score < 0.5 represents a trivial change, 0.5-0.9 indicates a small change, 1.0-1.4 demonstrate a 
moderate change, and ≥ 1.5 indicates a large change (5). 
 
The OSA-18 will be completed at the Baseline visit and 12 month follow-up. 
 
5.2.4 
In-Lab Titration Sleep Study: Polysymnography (PSG) 
Polysomnography will be conducted using standard techniques in the sleep laboratory.  The AASM 
(American Association of Sleep Medicine) Manual of Scoring Sleep, 2007 (6) is used as a guideline for rules, 
terminology and technical specifications for the PSG study.  Briefly, the following list of recordings will be 
collected. 
1. Three channels of electroencephalogram  
2. Chin electromyogram  
3. Two channels of electrooculogram  
4. A single bipolar modified Lead II for electrocardiogram  
5. Chest and abdomen belts for  respiratory effort measurement  
6. One oronasal thermal sensor to detect the absence of airflow for apnea  
7. One nasal pressure transducer for detection of airflow for hypopnea   
8. One finger oximeter to continuously monitor arterial oxygen saturation 
9. One position sensor to electronically determine position (supine, left, right, prone), or a means for 
documenting position 
10. One leg electromyogram to record leg movements 
 

 
 
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All signals will be recorded on a digital PSG system and scored by the sleep lab. Prior to the PSG, the patients 
will fill out, or respond to, a Pre-PSG Interview that contains questions about recent behavior that may affect 
sleep during the PSG.   
 
Note: If a PSG was completed within 18 months prior to study enrollment, study sites may use this PSG to 
determine eligibility for the study. At minimum, this PSG must follow AASM standards and must report AHI 
and > 25% of AHI attributable to central apnea as these are part of eligibility criteria. 
 
5.2.5 
Drug Induced Sleep Endoscopy (DISE) 
Sleep endoscopies are routinely performed by ENT surgeons prior to sleep surgery to assess the location and 
extent of collapse of upper airway anatomical structures.  Sleep endoscopy is typically performed in an 
operating room with the subject in the supine position.  A digital video of the sleep endoscopy will be 
recorded.  Continuous monitoring with electrocardiogram and oxygen saturation is performed.  Induction of 
artificial sleep is achieved by an anaesthetist (or physician with equivalent training) by means of intravenous 
administration of propofol and/or midazolam.  Anesthesia is titrated by targeting a level of light sedation 
such that the subject is arousable upon vocal stimulation.  
 
Anatomical collapse is evaluated at the level of the palate, oropharynx, tongue base, and epiglottis.  The 
degree of obstruction is characterized at each level as complete, partial, or none.  The type of collapse is also 
characterized at each level as concentric, antero-posterior (A-P) or originating from the lateral wall.  Subjects 
with complete concentric collapse at the level of the soft palate are not eligible for implant and exited from 
the study during pre-implant screening.   
 
If a DISE is performed as a standard-of-care procedure within 18 months prior to consent, and results 
(documented in the medical history) clearly state that subject did not have complete concentric collapse at the 
level of the soft palate, then the implant may be scheduled.  
 
A DISE must be performed after enrollment and before implant, if one did not occur within 18 months prior 
to signing consent.  The DISE may be performed immediately prior to the implant (during the same 
procedure as the implant).  This allowance is intended to prevent subjects from having to undergo an 
additional DISE procedure at centers where DISE is a standard assessment, when the DISE is likely to match 
a prior DISE result. 
 
All video recordings of the DISE procedures will be uploaded electronically both to a secure hospital-hosted 
file transfer system and to a secure Inspire-hosted website.  The video is then reviewed by a team of three 
specialist physicians, including the sponsor-investigator; at least two of the reviewing physicians must agree 
the subject is an appropriate candidate for surgery.  The three doctors are Dr. Christopher Hartnick from 
Massachusetts Eye and Ear Infirmary, Dr. Ryan Soose from University of Pittsburgh Medical Center and Dr. 
Raj Dedhia from the University of Pennsylvania.  If a DISE is to be performed just prior to surgery in order 
to decrease the number of times a subject is anesthetized, the physician reviewers will be alerted and available 
via phone to review the DISE in real-time.  The decision of the physicians was previously documented via e-
mail but as of version 9 of the protocol, a worksheet will be completed and signed by the sponsor-
investigator; any additional documentation provided by the other physician reviewers will be included with 
the worksheet. 
 
5.2.6 
Device Check  
Using the physician programmer, the general integrity of the system and subject use of the device will be 
verified.  In addition, stimulation threshold testing may be performed where by the stimulation amplitude is 
adjusted..  
 

 
 
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During sensor testing, the physician programmer displays the respiratory pressure signal, as well as the timing 
of stimulation pulses.  Adjustments can be made to the device sensing parameters (sensing thresholds and 
refractory periods) to synchronize stimulation with respiration.  For example, if stimulation starts late, after 
the start of inspiration, the sensing parameters are made more sensitive to the start of inspiration.  If the end 
of inspiration is not detected, then the sensing parameters detecting the end of inspiration are made more 
sensitive.   
 
The device should be interrogated at the beginning of the subject’s follow-up; and any programming changes 
that occur during the follow-up should be documented in the Device Check CRFs.  Information will also be 
collected about the subject’s use of the device since the last follow-up at each visit.  Information concerning 
any difficulties in operating the system, and sudden changes in the effects of the system, will be documented.   
 
Note: the Investigator will have received training on how to perform device programming, and will have the 
programmer technical manual available for reference.  Therefore, detailed programming steps are not 
included in this protocol. 
 
5.3 Study Visits 
5.3.1 
Screening / Baseline 
Screening and Baseline activities may occur over several clinic visits, and may include information and/or 
tests that were performed locally within 18 months prior to signing consent. After consent is obtained (either 
in person consent to participate in the study or, if allowed by the local IRB, remote consent for screening), 
medical records including the PSG will be reviewed by the local PI and the DISE video will be reviewed by 3 
person physician panel. If 2 of the 3 physicians agree the subjects is suitable, they will receive medical 
clearance for the surgery. The remainder of screening is to be completed by the local PI.  Parents of eligible 
children interested in participation will sign a questionnaire affirming that their child is able to communicate 
pain or discomfort, as well as their ability to monitor their child for development of adverse side effects 
related to implantation. 
 
At the baseline visit, consent to participate in the study will be obtained. After consent is obtained, a routine 
head and neck physical examination, including functional tongue exam will be performed.  Parents will 
complete OSA-18 and ESS questionnaires prior to surgery.  
 
5.3.2 
Surgery 
Prior to surgery, an institution specific surgical consent will also be completed by the parent and surgeon. On 
the day of implant before surgery the medication list will be reviewed and updated. Tongue movement and 
device function will be tested and documented at the time of implantation. A postoperative x-ray will be 
performed to document correct placement of the device. The device will remain off (turned “off,” voltage set 
to = 0) until the activation and titration appointments scheduled approximately 1 month after surgery. The 
postoperative course and postoperative analgesics required will be documented. 
 
A subject may undergo attempted implantation of the device, but the surgeon may be unsuccessful in placing 
the device.  If one or both leads cannot be placed, the incision (s) will be closed, and the stimulator will not 
be implanted.  The subject will return for a follow-up visit (usually within 14 days, but no greater than 30 days 
after attempted implantation). If no adverse event has occurred related to the surgery, the subject may be 
released from the study after the follow-up visit. 
 
5.3.3 
Standard of Care 1 Week Post-op Visit 
As part of standard clinical care, subjects will be asked to see an ENT physician for a post-op wound check. 
For out of state subjects and families, this may be done at their local ENT. No data will be collected at this 

 
 
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visit.  Subjects and their families will be instructed to call the study doctor if there are any issues noted at this 
visit or at any time during the study. 
 
5.3.4 
Device Activation and Initial Titration  
At approximately 1 month (± 14 days) after implantation (or 1 month ± 14 days after any wound issues that 
arise have resolved), subjects will be seen at the office and on the same day be scheduled for an in-lab PSG. 
The surgeon will reassess the wound, perform a functional tongue exam, review and update the medication 
list, and check the device.  The device will then be turned on and voltage adjusted to confirm that it is 
functioning.  Voltage will be turned down to 0. The subject will then undergo overnight in-lab PSG and 
settings on the device will be titrated.   
 
5.3.5 
Follow-up Study Visits 
5.3.5.1 
2 Month Follow-Up Visit 
Approximately 2 months (± 30 days) after implantation, the subject will be evaluated by the surgeon.  A 
limited physical exam, including functional tongue exam, will be performed. Medication reconciliation will be 
performed.  Any adverse events will be documented and submitted.  The OSA-18 and ESS questionnaires 
will be administered.  The device will be interrogated.  The subject will then undergo in-lab PSG and if 
necessary, further titration. This in-lab PSG may occur within 2 weeks of the follow-up visit or as 
appointments are available at each site’s sleep lab. However, all efforts should be made to keep the follow-up 
clinic visit and in-lab PSG as close as possible. 
 
5.3.5.2 
6 Month Follow-up Visit  
Approximately 6 months (± 30 days) after implantation, the subject will be evaluated by the surgeon.  A 
limited physical exam, including functional tongue exam, will be performed. Medication reconciliation will be 
performed.  Any adverse events will be documented and submitted.  The OSA-18 and ESS questionnaires 
will be administered.  The device will be interrogated.  The subject will then undergo in-lab PSG and if 
necessary, further titration. This in-lab PSG may occur within 2 weeks of the follow-up visit or as 
appointments are available at each site’s sleep lab. However, all efforts should be made to keep the follow-up 
clinic visit and in-lab PSG as close as possible. 
 
5.3.5.3 
12 Month Follow-up Visit  
Approximately 12 months (± 30 days) after implantation, the subject will be evaluated by the surgeon.  A 
limited physical exam, including functional tongue exam, will be performed. Medication reconciliation will be 
performed.  Any adverse events will be documented and submitted.  The OSA-18 and ESS questionnaires 
will be administered.  The device will be interrogated.  Mean weekly usage data will be recorded, and a record 
will be kept of the physician programmer readout as supporting source documentation. The subject will then 
undergo in-lab PSG and if necessary, further titration. This in-lab PSG may occur within 2 weeks of the 
follow-up visit or as appointments are available at each site’s sleep lab. However, all efforts should be made to 
keep the follow-up clinic visit and in-lab PSG as close as possible. 
 
5.3.6 
Unscheduled Visits 
Subject visits to the center related to implantation outside of regularly scheduled visits as part of the study will 
be documented.  If ineffective stimulation is noted, additional troubleshooting of the system may be required, 
or further investigations with in-lab PSG or DISE required.  The investigators will refer to system manuals or 
seek assistance from Inspire representatives for support regarding troubleshooting procedures. 
 

 
 
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5.4 Concomitant Medications and Procedures 
Subjects will continue their home medications during participation in the study, with the exception of 
NSAIDs or dietary supplements that increase the risk of bleeding in the immediate perioperative period (1 
week before implantation and 2 weeks post-implantation).  Subjects will receive standard anesthetics and 
postoperative pain medications.  Medication logs will be reviewed, updated, and documented at each 
postoperative visit.  General anesthesia in the Down syndrome population may cause increased risk of airway 
obstruction and bradycardia intraoperatively, as well as increases the risk of emergence agitation in the 
immediate postoperative period.  This will be discussed with families during the consent process, as well as 
on the day of procedures when anesthesiology obtains anesthesia consent. 
 
5.5 Participant Discontinuation / Withdrawal from the Study 
5.5.1 
Discontinuation of Device 
Discontinuation of device use or choosing not to use the device does not mean discontinuation from the 
study, and any remaining study procedures should be completed as indicated by the study protocol.  If a 
clinically significant finding is identified (including, but not limited to changes from baseline) after enrollment, 
the investigator or qualified designee will determine if any change in participant management is needed. Any 
new clinically relevant finding will be reported as an adverse event (AE). 
 
5.5.2 
Participant Withdrawal from the Study  
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
Pregnancy 
 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
 
Disease progression which requires discontinuation of the study intervention 
 
If the participant meets an exclusion criterion (either newly developed or not previously recognized) 
that precludes further study participation 
 
The reason for participant discontinuation or withdrawal from the study will be recorded. Subjects who sign 
the informed consent form, and are implanted, and subsequently withdraw, or are withdrawn or discontinued 
from the study, will be replaced. 
 
The DSMB may also determine whether participants should continue in the study as planned, proceed with 
modifications, or have their participation terminated.  The justification to terminate a subject’s participation 
may be due to the DSMB’s analysis that there is a concern for the subject’s safety or the subject’s ability to 
comply with study requirements. 
 
5.5.3 
Device Failure, Revision, and Explant 
5.5.3.1 
System Revision 
If the performance of the Inspire system remains unsatisfactory after troubleshooting, a replacement or 
adjustment to one or more components of the Inspire system (IPG, stimulation lead, or sensing lead) may be 
considered.  Specific guidance on removal or adjustment of implanted components is contained in system 
manuals.  The decision for replacement must be reviewed with the device manufacturer.  Explanted system 
components must be returned to the device manufacturer.  If the therapy is abandoned, device removal will 
be discussed with the subject as described in the following section. 
 

 
 
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5.5.3.2 
System Explant 
The system may be explanted at any time during the study.  Subjects may request that their device be 
removed due to discomfort of components, infection, erosion, or subject may not respond to the therapy and 
elect removal. 
If the device is removed, the following CRFs must be completed. 
 
Adverse Event Form 
 
Updates to Medication Log  
 
5.5.3.3 
System Explant Post-Op Check 
Following removal of the device or components, the subject will be seen 1 week (4-14 days) after revision or 
removal to check the subjects’ well-being and examine the wound post-operatively.   
The following CRFs will be completed during the Post-Op check: 
 
Physical Exam 
 
Updates to Medication Log 
 
Adverse Event Form (if applicable) 
 
5.5.3.4 
Disposition of Device Following Study Withdrawal 
Subjects who withdraw from the study will need to discuss with their physician the disposition of their 
implanted system.  Upon withdrawal from the study, the subject may continue with the use of the therapy, 
and should consult with the physician regarding long-term management with the therapy. 
 
Investigators should discuss expectations with subjects who withdraw from the study including: 
 
MRI imaging of the chest may NOT be performed when system components are implanted.  
However, MRI imaging of the head and extremities may be performed as needed according to 
specific parameters. 
 
Inform personal physicians, consulting physicians, or dentists that a stimulation system is implanted. 
 
Carry the Inspire Medical Systems patient ID card at all times. 
 
Consult the study physician or the device manufacturer if the following medical treatments are 
required:  dental procedures requiring a drill, surgery with electrocautery, irradiation therapy, 
lithotripsy, RF-ablation, high output ultrasonic therapy, other implantable stimulation therapy, or 
defibrillation.   
 
5.5.4 
Participant Lost to Follow-up 
A participant will be considered lost to follow-up if he or she fails to return to the clinic within 3 months of 
their scheduled visits and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
 
The site will attempt to contact the participant and reschedule the missed visit bi-weekly for 3 
months and counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study. 
 
Before a participant is deemed lost to follow-up, the investigator or designee will make every effort 
to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a certified 
letter to the participant’s last known mailing address or local equivalent methods). These contact 
attempts should be documented in the participant’s medical record or study file.  
 
Should the participant continue to be unreachable, he or she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up. 
 

 
 
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6 Study Device 
The Inspire system was developed to treat moderate to severe OSA (15 ≤ AHI ≤ 65) in adult patients who 
are not effectively treated by CPAP. The Inspire system is comprised of the following components (Figure 1): 
 
Inspire II Upper Airway Stimulator, Model 3024 (Implantable Pulse Generator, IPG) and any 
subsequent iteration thereof that are approved under P130008 for the treatment of obstructive sleep 
apnea which are listed below and updated as needed via protocol modifications submitted to the 
FDA.  Note: Inspire Model 3028 IPG received FDA approval on May 5, 2017 and replaces Model 
3024 IPG. 
 
Inspire Stimulation Lead, Model 4063 (stimulation lead) 
 
Inspire Sensing Lead, Model 4323 (sensing lead) 
 
External programmers used with the system are: 
o Inspire Programmer, Model 2740 (physician programmer) 
o Inspire Patient Programmer, Model 3032 (patient programmer) 
 
 
When the device is on, the Inspire system detects the patient’s respiratory effort and maintains airway patency 
with mild stimulation of the hypoglossal nerve. 
 
Device settings are stored in the IPG and configured by the physician using an external programmer. 
The patient uses their Inspire sleep remote to turn the device on before they go to sleep and to turn therapy 
off when they wake up. The sleep remote also provides the ability to pause therapy and adjust stimulation 
amplitude within physician defined limits. 
 
6.1 
Device Components 
The implanted components of the Inspire system consist of an Implantable Pulse Generator (IPG), a 
respiratory sensing lead, and a stimulation lead. All implanted Inspire system components are intended for 
single-use only. 
6.1.1 
Implantable Pulse Generator (IPG) 
The IPG (Figure 2) contains the battery and electronics that deliver Inspire therapy and store the therapy 
settings. 
 

 
 
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The IPG has two 3.2 mm low-profile connector ports (Figure 3), which are compatible with the connectors 
on the stimulation lead and the respiratory sensing lead. After inserting the lead connectors into the IPG 
connector ports, the lead connectors are secured using the set screws next to the connector ports. 
 
 
Only study investigators will perform device implantation surgery. In order to become certified to implant the 
Inspire device, all participating surgeons will need to complete a training program, including cadaveric 
dissections, offered by Inspire Medical Systems.  This training program will also include modules on how the 
device is activated and programmed.    
 
Sleep medicine physicians and involved technicians will also complete training on device programming and 
titration based upon sleep study results.   
 
Using the physician programmer function on the device the general integrity of the system and subject use of 
the device can be verified.  The device will be interrogated at the 2 month, 6 month and 12 month visits, as 
well as at any unplanned visits.  Programming changes, difficulties operating the system, or any sudden 
changes in the system’s effects will be documented in the subject’s case file. 
 
Parents will be instructed on how to use the programmer to turn the device on/off and change settings by 
certified staff during activation, follow-up appointments, and during sleep studies. 
 
Any adverse events that occur during baseline or screening procedures will be documented on the Adverse 
Event Form and submitted for review. 
 
Refer to the System Implant Manual as well as the Patient Programmer Manual for details about the device, 
implant training, and system use.  
 

 
 
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6.2 Acquisition and accountability 
Each site will be authorized to begin enrolling subjects and order study devices once all appropriate regulatory 
documentation has been collected.  The study devices will be ordered based on each site’s study device 
accountability plan. The devices will not arrive labeled, as Inspire is shipping devices from their clinical stock.  
Each site must label the device “CAUTION – Investigation device. Limited by Federal (or United States) law 
to investigational use” and document that the device has been labeled appropriately.  
 
Devices must be stored in a secure (locked) area at room temperature. Access should be limited to designated 
study staff only. Device accountability logs will be provided to the site. It is the site’s responsibility to 
document the receipt (including maintain shipping logs), disposition of the product (per subject use, including 
serial number of device used, serial number of remaining devices, etc.), transfer (if applicable) and return of 
all unopened study devices. This information must also be provided to the sponsor-investigator for 
recordkeeping purposes. 
6.3 Product Storage and Stability 
Inspire Medical Systems sterilizes the IPG and leads with ethylene oxide (EtO) prior to shipment.  
6.3.1 
IPG 
Inspect the IPG sterile package prior to opening. If the IPG package is damaged, the IPG may be damaged as 
well. Return a damaged package to Inspire Medical Systems.  The IPG box includes a sterilization indicator. 
This indicator is green after the device has been sterilized. Do not use the IPG if the indicator is red. 
 
See Table 1 for IPG Storage and Handling 
 
Table 1. IPG Storage and Handling 
Handling and Storage: Acceptable 
Unacceptable 
Store and transport IPG within the following 
environmental temperature limits: -35 °C (-31 °F) 
to +58 °C (+136 °F). A full or partial electrical 
reset condition may occur at temperatures below -
18 °C (0 °F) 
Do not implant the IPG if it has been dropped on a 
hard surface from a height of 30 cm (12 in) or 
greater 
Resterilization  
 
The IPG cannot be resterilized. 
 
IPGs cannot be resterilized. If the sterile 
package seal is broken, or if the packages 
are otherwise damaged, do not use.  
 
Return the package to your local Inspire 
Medical Systems representative, see back 
cover for address.  
 
 
6.3.2 
Leads 
If the lead sterile package seal is broken or the package is otherwise damaged, return the package to Inspire 
Medical Systems. Leads cannot be resterilized. 
 
See Table 2 for Leads Storage, Handling, and Resterilization. 
 

 
 
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Table 2. Lead Storage and Handling 
Handling and Storage: Acceptable 
Unacceptable 
Store and transport leads within the following 
environmental temperature limits: -10 °C (14 °F) to 
+55 °C (131 °F).  
Only use sterile-gloved hands to handle the lead; 
rinse sterile surgical gloves in sterile water before 
handling the lead.  
Protect leads from materials that shed lint and dust.  
Exercise care and appropriate instrument selection 
when handling the stimulation lead cuff with a 
surgical instrument.  
Do not implant a lead that was dropped 
Avoid excessive traction or sharp instruments 
Avoid severe bending, kinking, stretching, or 
handling with surgical instruments.  
Do not immerse a lead in mineral oil or silicone oil. 
Resterilization  
 
Leads cannot be resterilized. 
 
If the sterile package seal is broken, or if 
the packages are otherwise damaged, do 
not use.  
 
Return the package to your local Inspire 
Medical Systems representative, see back 
cover of this manual for addresses.  
 
 
7 Risks and Benefits 
7.1 
Known Potential Risks 
7.1.1 
Risks of Screening Procedures 
7.1.1.1 
Risks of Drug-Induced Sleep Endoscopy (DISE) 
 
Nose bleeding 
 
Trauma to the upper airway 
 
Suspension of breathing episode 
 
Light-headedness 
 
Pain or irritation in the throat or nasal passage 
7.1.1.2 
Risks of PSG Studies 
 
Inability to sleep in the PSG lab 
 
Irritation or bleeding at external electrode sites 
 
Bruising or bleeding or soreness from external electrode removal 
 
Fatigue the next day, loss of productivity 
 
May lead to pain or sleeplessness 
 
7.1.2 
Risk of Implantation Surgery 
The surgical scar will be approximately 2 inches long, just below the chin.  Normally this scar blends in with 
normal creases in the neck and is not disfiguring.  The electrodes and sensor should not be noticeable 
underneath the skin.  The stimulator may cause a small lump underneath the skin below the collar bone. 
 

 
 
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A minority of OSA patients also have other neurological causes of sleep apnea, called "central sleep apnea". If 
improvement in the subject’s OSA by the implanted nerve stimulator reveals this other type of apnea, 
additional treatment during and after his/her hospitalization may be necessary. 
 
7.1.2.1 
Surgical Related Risks 
 
Post-surgical pain or tenderness near incisions 
 
Post-surgical headache, fever, or dizziness 
 
Post-surgical throat soreness from intubation 
 
Post-surgical nausea or vomiting 
 
Post-surgical irritability, nervousness, confusion   
 
Post-surgical sleep problems like insomnia or sleepiness 
 
Post-surgical constipation 
 
Post-surgical mild to moderate swelling, oozing, and/or bruising around the surgical incisions, 
 
Post-surgical back pain due to lying on the table during the procedure 
 
Depending on geography, standard uncomplicated post-implant hospitalization may be up to 36 
hours.   
 
Damage to blood vessels (e.g. erosion) in the vicinity of implant  
 
Allergic and/or rejection response to the implanted materials 
 
Excessive bleeding  
 
Infection 
 
Trauma (e.g. perforation or dissection) or damage to arteries and veins  
 
Local irritation, infection, seroma (pocket of clear fluid under the skin, hematoma (blood outside the 
blood vessels), erosion, swelling 
 
Irritation or damage to nerves near the implant 
 
Persistent pain at the implant site 
 
Nerve trauma  Pain, numbness or inflammation in the mouth, neck 
 
Hypoglossal nerve trauma or damage  
 
Strange sense of touch or burning sensation on the tongue or neck (dysesthesia) 
 
Procedure related deterioration of pre-existing medical condition 
 
Tongue movement restrictions 
 
Blood thinning medications may result in complications such as excessive bleeding, clotting, or 
hematomas 
 
Tongue may get larger (hypertrophy) or smaller (atrophy) 
 
Airway constriction or obstruction 
 
Tongue muscle twitches (Fasciculations) 
 
Air in the chest cavity (pneumothorax) 
 
Problems with swallowing or speaking 
 
Damage to the lung or membrane that surrounds the lung (pleura) 
 
Muscle stimulation of floor of mouth musculature 
 
Death Pneumothorax 
 
7.1.2.2 
Risks of Anesthesia 
Drug induced sleep endoscopy, surgical implantation, battery replacement, electrode repositioning and device 
implantation will be performed under anesthesia.  General anesthesia can result in airway obstruction, 
temporary changes in heart-rate and oxygen level, and changes in behavior as medications wear off. These 
risks are increased in subjects with Down syndrome.   

 
 
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7.1.2.3 
Device Complications/Malfunctions 
 
Migration or traction of pulse generator or leads  
 
Elevated stimulation threshold 
 
Lead dislodgement 
 
 
Failure to stimulate 
 
Lead damage and/or failure  
 
 
Implantable Pulse Generator failure 
 
Premature battery failure  
 
 
Failure of respiratory sensing 
 
Breakage or misuse of surgical tools 
 
 
Misuse of the subject programmer may result in ineffective function 
 
Spontaneous stimulation and sensing threshold changes  
 
 
Therapy may irritate a subject, wake them, or prevent them from sleeping 
 
MRI can induce currents on implantable components, potentially causing tissue damage and tongue 
dysfunction 
 
 
MRI may cause damage to the device 
 
Should your child become pregnant, there may be unknown risks to the embryo or fetus 
 
 
There may be risks that are not currently known at this time 
 
Implanted parts may need to be surgically moved or removed 
 
7.1.2.4 
Potential Need for More Surgery 
Battery replacement: The implanted device is powered by a battery that has an expected lifespan of 5-8 
years.  The lifespan of the battery will vary based on the stimulation parameters that the investigator programs 
into the subject’s device. Although unlikely, the battery may deplete sooner than expected.  Battery 
replacement is performed through a small incision at the device implant site below the subject’s collar bone 
under local anesthesia, where a numbing medication is injected into the tissue over the implant.   
 
Repositioning or replacement of stimulation or sensing leads: If one of the implanted leads moves, the 
investigator may need to perform another surgery to reposition or replace the lead in order for the subject to 
continue to use the device.  Risks related to another surgery are described in the potential risk section (table), 
as well as sections on considerations for implanted device removal and potential risks associated with 
implanted device removal. 
 
7.1.3 
Pregnancy Risks 
A female subjects may not take part in the study if she is pregnant or has plans to become pregnant during 
the study period due to procedures that require general anesthesia.  All female subjects aged 11 and up will 
undergo urine beta-HCG testing on the day of procedures requiring general anesthesia (DISE, implantation, 
and any other unanticipated surgical procedures related to implantation).  Subjects who are positive will not 
undergo surgical implantation or procedures under general anesthesia. 
 
7.1.4 
Psychosocial (non-medical) Risks 
Subjects may experience distress regarding discomfort from the surgery or device.  
 
7.1.5 
Considerations for Future Medical Care 
Strong magnetic fields generated by magnetic resonance imaging (MRI) scanners may move the stimulation 
device, leads, or cause excessive stimulation.  After the device is implanted, the subject will not be able 

 
 
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to have an MRI scan of the chest, but will able to get MRI imaging of the head and extremities 
ONLY according to specific parameters. Other available testing methods, such as CT scan, ultrasound, 
and X-ray, which will not interfere with the implanted device should be considered.  If an MRI scan is needed 
of the chest, the Inspire® system must be removed surgically.  
 
Precautions must be taken around theft and security detectors (such as those found in museums, retail stores, 
courthouses, and airports).  The magnetic fields created by this equipment could cause the implanted device 
to stimulate the subject’s tongue.  In rare cases, they could also reset the device to zero volts.  If this 
happened, it would become clear the next time the subject tried to use the device. When the remote is 
positioned above the subject, it will beep if the device is working properly; it will not beep if the device has 
been reset to zero volts.  Should the device be reset, the subject will need to see the doctor to have the device 
reprogrammed. 
During the course of the subject’s life, additional implantable devices such as cardiac defibrillators or 
pacemakers may need to be placed.  The nerve stimulator might interfere with functioning of these devices.  
Therefore, it is important that any doctor taking care of the subject know about the nerve stimulator that is 
implanted.  The treating doctor should contact the investigator of this trial prior to any procedure to ensure 
that the subject’s implanted device remains safe. 
 
A wallet card and laminated letter will be provided to subjects identifying them as having this implant.  
Written instructions will be provided to families detailing important information dentists and other surgeons 
should know when providing medical care to the subject. 
 
7.2 Known Potential Benefits 
Based on previous studies with the adult population, it is expected that the device will improve sleep in a 
majority of the enrolled subjects. Furthermore, subjects in this study may benefit from additional contact with 
clinicians and medical testing that could lead to early detection of and or advanced treatment of a medical 
condition that was not previously diagnosed.   
 
8 Data Safety and Monitoring 
8.1 
Data Safety and Monitoring Board 
The Data and Safety Monitoring Board (DSMB) will serve as the independent data and safety monitoring 
board for this study. The DSMB will meet regularly as laid out in the DSMB charter to review progress of the 
study and will be available for emergent meetings if serious or unanticipated adverse events occur. The 
serious adverse events and responses will be reviewed by the DSMB. 
8.2 Research monitor 
The chair of the DSMB will also serve as the Research Monitor. The Research Monitor will review all 
unanticipated problems involving risks to subjects or others associated with the protocol and provide an 
independent report of the event to the IRB. The Research Monitor may discuss the research protocol with 
the investigators; shall have authority to stop a research protocol in progress, remove individual human 
subjects from a research protocol, and take whatever steps are necessary to protect the safety and well-being 
of human subjects until the IRB can assess the monitor's report; and shall have the responsibility to promptly 
report their observations and findings to the IRB or the Data Safety and Monitoring Board (DSMB). 
8.3 Regular Site Monitoring 
An external monitor will be contracted by the sponsor-investigator to do on site monitoring. This monitoring 
will be done at regular intervals as outlined by the Monitoring Plan to ensure study compliance with the 
protocol and all applicable laws, regulations, and guidelines.  

 
 
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8.4 Adverse Event Monitoring and Reporting  
All adverse events (AEs) will be documented in a timely manner throughout the clinical trial and reported in 
the database.  All events will be reported to the PI, FDA, and DSMB. The sponsor-investigator has 
established procedures in conformity with worldwide regulatory requirements to ensure appropriate reporting 
of safety information.  This study is conducted in accordance with these procedures and regulations.  All 
adverse events and adverse device effects will be reported in all geographies.  Reportable adverse events will 
be monitored prospectively from enrollment (consent) to the end of the follow-up period. For the purposes 
of this study, reportable AEs include all events meeting the definition of “serious” as well as any 
events possibly related to the study procedures, study device, therapy or required testing. See Figure 
4 (Classification of Adverse Events) to determine whether in AE is reportable. 
 
8.4.1 
AE Definitions for Investigator Classification 
Investigators are responsible for categorizing adverse events according to their seriousness and relatedness 
(e.g., to the surgical procedure, to the Inspire system, etc.).  The Sponsor will then review all reported adverse 
events for completeness, and ask for clarification or additional information if necessary.  The definitions for 
classifications are included below and on the provided adverse event log.  Those events that do not meet the 
criteria for Serious Adverse Event are considered non-serious.  
 
8.4.1.1 
Adverse Event 
An Adverse Event (AE) is any undesirable subject event that occurs during the course of the study, from 
consent through exit.  For the purpose of the study, reportable AEs include all events meeting the definition 
of “serious” as well as any events possibly related to the study procedure, study device, therapy or required 
study testing.  
 
8.4.1.2 
Serious Adverse Event  
Serious AEs will be identified as such on the AE CRF and defined as any adverse experience that results in 
any of the following outcomes:   
 
Death 
 
A life-threatening adverse experience 
 
In-patient hospitalization or prolongation of existing hospitalization 
 
A persistent or significant disability/incapacity 
 
Congenital anomaly/birth defect 
 
Important medical events that may not meet one of the above definitions could be considered SAEs 
if they jeopardize the health of the subject or require surgical intervention to prevent one of the 
outcomes listed in the definition above.  Serious adverse events may or may not be related to the 
procedure, system or therapy.  
 
8.4.1.3 
Unanticipated Adverse Device Effect 
An unanticipated adverse device effect (UADE) is any event on the subjects’ health, safety, or welfare not 
previously identified in nature, severity, or degree of incidence in the investigator’s brochure and 
investigational plan.  A serious device-related AE which is not identified as a potential complication in the 
labelling, and is unanticipated, adverse, and a consequence of the use of the Inspire system, must be reported 
to the sponsor as soon as possible, but in no case greater than five working days from the first knowledge of 
the occurrence.  The sponsor-investigator will coordinate with the site Investigator on the submission of 
specific clinical documentation appropriate to the UADE encountered.  In addition, written notice must also 
be supplied to the sponsor and reviewing IRB within 10 working days. 
 

 
 
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Any unanticipated adverse effects will be investigated immediately and if unreasonable risk to the patient 
population is not preventable, the study will be terminated and all regulating authorities and participating 
investigators will be notified.  Termination shall occur not later than 5 working days after the Sponsor makes 
this determination and not later the 15 working days after the Sponsor first received notice of the effect.  A 
terminated investigation may not be resumed without IRB approval. 
 
8.4.2 
Adverse Event Reporting 
All procedure and device related events will be collected during this study.  In addition, all adverse events 
meeting the definition of ‘serious’ (Section 10.12) are required to be reported.  All reportable adverse events 
are to be recorded on the AE CRF at the time of the occurrence(s) or at the time the Investigator becomes 
aware of the occurrence(s).  Additional information, such as procedural notes, operative notes, or a signed 
clinical summary may be required as supporting documentation for the reported AE.  All identifying 
information should be removed from these supportive documents and the subject’s study number should be 
used. 
 
All adverse events must also be described by: duration (onset and resolution dates); severity; relationship to 
the procedure, device or therapy; action taken to resolve the event; the outcome of the event and if it meets 
the definition of ‘serious’.  In addition a code will be assigned to the event based on type of relationship 
determined.  Relationship categories and codes are described below. All adverse events should be followed 
until the adverse event has been resolved, the subject has reached maximum medical improvement with no 
further actions to be taken, the subject exits the study, or until study closure, whichever occurs first. 
 
The timeframe for reporting of serious or unexpected AE’s to the Sponsor and governing IRB is presented in 
the table below (Table 3):  
 
Table 3:  Reporting requirements and Timeframe for SAEs and UADEs 
Type of AE 
Reporting Timeframe 
SAE 
Notify sponsor-investigator as soon as possible, with full 
report no later than 10 working days of occurrence or sites 
knowledge 
UADE 
Notify sponsor-investigator as soon as possible, with full 
report no later than 10 working days of occurrence or sites 
knowledge 
Death 
Notify sponsor-investigator within 24 hours 
 
8.4.2.1 
Relationship 
Investigators are also responsible to categorize adverse events according to their relatedness.  The definitions 
for relatedness classifications are included below.   
 
8.4.2.1.1 
Surgery Related 
A surgical related adverse event is any adverse event that is related to or possibly related to the surgical 
procedure to implant the device. These events typically occur within 30 days of surgery. Examples include 
significant bleeding during surgery, infection, acute tongue weakness.  
 
Any normal and expected postoperative complaints or symptoms are not required to be reported, unless the 
event involves a clinically significant change in severity or duration of symptoms or requires clinical 
intervention that is different from ordinary postoperative care. Expected postoperative care outcomes 
include: headache, incisional pain, nausea, vomiting, low grade fever, oozing at dressing, dizziness, irritability, 
nervousness, temporary sleep problems like insomnia or sleepiness, constipation, confusion and similar 

 
 
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events, tenderness, throat soreness secondary to intubation, or mild to moderate swelling and/or bruising 
around the implant site, back pain due to lying on the table during the procedure.  
 
8.4.2.1.2 
Device Related 
A device related adverse event is any adverse event that is related or possibly related to use of the device. 
Examples include device-related injection, undesirable change in stimulation (e.g. jolting or shocking), chronic 
or intermittent tongue soreness, discomfort, or intense stimulation. Acute events that occur during a device 
check that subside once acceptable parameters are selected are not reportable.  
 
8.4.2.1.3 
Other Protocol Testing or Evaluation Related 
Other procedures required as part of the study protocol but not associated with an Inspire system implant or 
Inspire device, that result in an AE.  Examples include: sore neck from in-lab PSG; nausea from anesthesia 
during DISE, etc. 
 
8.4.2.2 
Degree of Intensity / Severity 
In addition, investigators will categorize the intensity / severity of all AEs CRF as: 
Mild: 
 
Awareness of event, but easily tolerated 
Moderate:   
Discomfort enough to cause interference with usual activity 
Severe:   
Inability to carry out usual activity 
This determination is distinct and separate from the determination of whether or not an event is an adverse 
event (AE) or a serious adverse event (SAE). 
 
8.4.3 
Anticipated Adverse Device-Related Events 
Anticipated device related AEs (medical change from baseline), which may possibly be seen during this study, 
include the following presented in Table 4 (below), as reported in the PMA submission for 126 implanted 
subjects. 
 
Table 4:  Anticipated Adverse Device-Related Events 
Adverse Event 
Total Number 
of Events 
% of Subjects 
(n) 
N=126 
Discomfort due to electrical stimulation 
66 
33% (42) 
Temporary 
Tongue 
weakness 
or 
deviation 
35 
18% (23) 
Tongue abrasion 
23 
16% (20) 
Mechanical pain associated with presence 
of device 
6 
5% (6) 
Infection (mild or moderate) 
1 
1% (1) 
 
8.4.4 
Technical Observation/Device Deficiencies 
All device deficiencies related to the identity, quality, durability, reliability, safety, or performance of an 
investigational device shall be documented throughout the investigation.  Device deficiencies that did not lead 
to an adverse event but could have led to a medical occurrence shall be reported including if suitable action 
had not been taken, intervention had not been made, or circumstances had been less fortunate. 
 
User Error: An instance where an act or omission of an act results in a different medical device response 
than intended by the manufacturer or expected by the user is considered a ‘user error’.  This includes slips, 

 
 
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lapses and mistakes.  An unexpected physiological response of the subject does not in itself constitute a use 
error. 
 
8.4.5 
Subject Death 
A subject death during the study must be reported to Sponsor as soon as possible.  Notification of death 
must include a detailed narrative that provides detailed information describing the circumstances surrounding 
the death and is signed by the Principal Investigator or authorized co-Investigator.  The death letter should 
include the following information:  
 
Date and time of death 
 
Place death occurred 
 
Immediate cause of death 
 
The relatedness of the death to the Inspire system, surgical procedure, neurostimulation, clinical 
investigation, or subject condition. 
 
Whether or not the death was witnessed 
 
Device status and/or activity at the time of death  
 
Any other circumstances surrounding the death 
 
The PI or co-Investigator must sign and date the letter.  If information listed above that is unavailable or 
unknown must be specified in the death letter. Also the following documentation should be obtained: 
 
If the subject expired in the hospital, a copy of the medical records for that admission (e.g., H & P, 
consults, test results, operative reports, and/or progress notes from the hospital chart) 
 
Death certificate (if available) 
 
Autopsy report (if applicable) 
 
The study exit CRF will be completed and any open events will be formally closed in the database (outcome: 
death).  Whenever possible, the pulse generator should be interrogated. Study devices and related Sponsor 
system components (e.g., leads) should be removed intact and returned promptly to Sponsor for analysis.   
 
9 Statistical Considerations  
9.1 
Primary endpoint(s) or outcome measure(s) 
 
The primary endpoint of this pilot study is to assess the safety of hypoglossal nerve stimulator 
placement for the treatment of obstructive sleep apnea in adolescents with Down Syndrome. 
 
Safety of implantation will be monitored throughout the perioperative period and unanticipated and 
anticipated adverse device related events will be recorded. 
9.2 Secondary endpoints or outcome measure(s) 
 
The secondary endpoint of this study is to assess the efficacy of hypoglossal nerve stimulator 
placement in this patient population. 
 
Effectiveness in the treatment of obstructive sleep apnea will be measured using standard in-lab PSG 
measures, including oxygen level, partial and complete airway obstruction, and arousals.  
Improvement will be defined as a 50% or more decrease in AHI.  This will be measured prior to 
implantation, and compared to post-implantation values at 2 months, 6 months, and 12 months. 
 
Compliance will be assessed by objective data gathered by the device, which will be downloaded 
using the physician programming function at follow-up visits. 

 
 
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 
Quality of life improvements will also be measured using the OSA-18 questionnaire and Epsworth 
Sleepiness Scale.  Assessments will be performed preoperatively then at 2 months, 6 months, and 12 
months. 
9.3 Sample Size Determination 
This is a pilot study designed to assess if the hypoglossal nerve stimulator can be safely implanted and utilized 
by adolescents with Down syndrome. Up to forty-two (42) adolescents and young adults will undergo 
implantation for this study.  If implantation can be safely performed in this population, further studies will be 
designed and powered to assess for significant changes on PSG and quality of life with device usage. 
9.4 Analysis Population  
The pilot study population is designed as part of a preliminary efficacy study and will be utilized in the 
statistical evaluation of study endpoints. 
9.5 Effectiveness Analysis (if applicable) 
 
Pre and post-implantation quality of life scores and polysomnogram values will be used to assess the 
effectiveness of hypoglossal nerve implantation in the treatment of obstructive sleep apnea in 
adolescents with Down Syndrome.  
 
Any deviations from the previously described statistical plan will be described and justified in a 
protocol amendment and/or in the final report submitted to this application. 
9.6 Safety Analysis 
Anticipated and unanticipated adverse events related to device implantation will be recorded prospectively, 
examined and reported. 
10 Ethical Considerations  
10.1 Review by an Institutional Review Board 
Prior to initiation of the research described in this document, it will be reviewed by an institutional review 
board as required by 21 CFR 56.  
 
10.2 Informed Consent  
Prior to enrolling any potential subject or performing any non-standard of care study procedures, all potential 
subjects will be consented as required by 21 CFR 50.  
10.2.1 Inclusion of Minors 
As this study will enroll minors between the ages of 12 and 17, care will be taken to ensure the rights of this 
subject population. Both parents/guardians of the potential subject will be consented unless one parent is 
deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal 
responsibility for the care and custody of the child.. Of note, it is possible that one parent may not be 
reasonably available due to inability to travel to a study site based on financial restrictions or other logistical 
concerns such as childcare for other children, job requirements, etc. In such cases, both parents will discuss 
the study with the local PI via telephone and those discussions will be documented, along with the reason 
that one parent will not be available to sign consent in person on the day of consent. 
 
Additionally, the underage subject themselves will also be assented. Written assent is preferred, but verbal 
assent will be obtained and documented in cases where the subject’s maturity and/or ability make obtaining 
written consent infeasible. If the underage subject turns 18 during the course of the study, and they are 
capable of providing consent for themselves, they will be re-consented, as they can determine for themselves 
if they wish to continue to participate in the study.  If an underage subject turns 18 and is not capable of 

 
 
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providing consent for themselves, the previously obtained parental permission and assent will remain 
effective and this determination will be documented in the medical record and study record.  
10.2.2 Inclusion of Persons not Competent to Consent 
As this study will enroll subjects with Down syndrome up to age 21, care will be taken to ensure the rights of 
adult subjects, 18 and older, who are not competent to consent. If an adult subject is deemed incapable of 
providing consent, two parent/guardian consent and subject assent will be obtained as with pediatric subjects 
on this trial.  
10.2.3 Non-English Speaking Subjects  
As this is a pilot study with a significant risk device, all subjects and their parents must be able to 
communicate questions and concerns to the study staff at all times. All subjects and all parents must be 
proficient in English for this to occur. In further studies, we plan to expand study materials and resources in 
order to include patients who are non-English speaking. Given the small scale of this pilot study, we feel 
initial exclusion of non-English speaking individuals should not adversely affect applicability of our results to 
the general population, nor should it prevent all qualified patients from eventual access to device 
implantation. 
10.3 Statement of Compliance  
This study will be performed in compliance with all applicable federal, state, and local regulations and 
requirements for the protection of human subjects in a clinical trial.  
References  
(1) Diercks GR, Keamy D, Kinane TB, et al. Hypoglossal Nerve Stimulator Implantation in an 
Adolescent With Down Syndrome and Sleep Apnea. Pediatrics. 2016;137(5):e20153663 
(2) Diercks GR, Wentland C, Keamy D, et al. Hypoglossal Nerve Stimulation in Adolescents With 
Down Syndrome and Obstructive Sleep Apnea. JAMA Otolaryngol Head Neck Surg. 
2018;144(1):37–42. doi:10.1001/jamaoto.2017.1871 
(3) Caloway, C. L., Diercks, G. R., Keamy, D. , de Guzman, V. , Soose, R. , Raol, N. , Shott, S. R., 
Ishman, S. L. and Hartnick, C. J. (2019), Update on hypoglossal nerve stimulation in children with 
down syndrome and obstructive sleep apnea. The Laryngoscope. doi:10.1002/lary.28138\ 
(4) Johns MW, A New Method for Measuring Daytime Sleepiness: The Epworth Sleepiness Scale. Sleep, 
14(6):540-545. 
(5) Franco RA Jr, Rosenfeld RM, RaoM. Quality of life for children with obstructive sleep apnea. 
Otolaryngol Head Neck Surg. 2000;123(1, pt 1):9-16. 
(6) Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy of Sleep Medicine.  The 
AASM Manual for the Scoring of Sleep and Associated Events:  Rules, Terminology and Technical 
Specifications, 1st ed.:  Westchester, Illinois:  American Academy of Sleep Medicine, 2007.