A Pilot Study to Evaluate the Hypoglossal Nerve Stimulator in Adolescents With Down Syndrome and Obstructive Sleep Apnea

• ClinicalTrials.gov Identifier: NCT02344108
• Recruitment Status: Completed
• First Posted: January 22, 2015
• Results First Posted: February 11, 2022
• Last Update Posted: April 12, 2022
• Sponsor: Christopher Hartnick, M.D.
• Collaborators: Emory University; Children's Hospital Medical Center, Cincinnati; Inspire Medical Systems, Inc.; University of Pittsburgh; Children's Hospital of The King's Daughters
• Information provided by (Responsible Party): Christopher Hartnick, M.D., Massachusetts Eye and Ear Infirmary

Study Description

Brief Summary:

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 a 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, adenotonsillectomy (T&A) 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, and any subsequent iteration thereof that are approved under P130008 for the treatment of obstructive sleep apnea, which has already been approved for use in adults with OSA, can be safely implanted and used in adolescents and young adults with Down Syndrome.

Condition or disease	Intervention/treatment	Phase
Sleep Apnea, Obstructive; Down Syndrome	Device: Inspire® Upper Airway Simulation System (Model 3028 IPG )	Not Applicable

Detailed Description:

The study will be a multi-center, prospective, single-arm study conducted under a common implant and follow-up protocol. Twenty-one adolescents and young adults (10-21 years of age) with Down Syndrome with moderate to severe obstructive sleep apnea after adenotonsillectomy will be identified through a Multi-Disciplinary clinic for patients with Trisomy 21 at each of our participating sites Patients and their parents will be screened by a senior pulmonologist and pediatrician for medical clearance and willingness to participate. Subjects will then undergo preoperative evaluation with an in-lab polysomnogram (PSG), evaluation by a pediatric otolaryngology surgeon, and drug induced sleep endoscopy (DISE) to ensure all inclusion and exclusion criteria are met. Subjects meeting eligibility criteria will then be implanted with the Inspire® Upper Airway Simulation System, Model 3024 IPG, and any subsequent iteration thereof that are approved under P130008 for the treatment of obstructive sleep apnea, a hypoglossal nerve stimulator, after informed consent. Surgery will be performed by senior 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, then on an annual basis, 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 42 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: February 2015
• Actual Primary Completion Date: July 23, 2021
• Actual Study Completion Date: September 2, 2021

Arms and Interventions

Arm

Intervention/treatment

Experimental: Inspire® Upper Airway Simulation System; Subjects meeting inclusion criteria, including sleep study and drug induced sleep endoscopy criteria, will undergo surgical placement of a hypoglossal nerve simulator (Inspire® Upper Airway Simulation System Model 3028 IPG). The simulator will be activated one month after surgery and subjects will undergo repeat sleep study evaluation and device titration at one, two, six and twelve months after implantation. Subjects will be followed for one year to determine safety and efficacy of the device.

Device: Inspire® Upper Airway Simulation System (Model 3028 IPG ); Subjects will be implanted with a hypoglossal nerve stimulator. Safety and efficacy of implantation will be evaluated.; Other Name: hypoglossal nerve stimulator

Outcome Measures

Primary Outcome Measures :

1. Serious Adverse Events [ Time Frame: 1 year ]
   In this study, adverse events were defined as "serious" if they resulted in: (1) death; (2) a life-threatening experience; (3) in-patient hospitalization or prolongation of hospital stay; (4) a persistent or significant disability/incapacity; (5) congenital anomaly/birth defect; or (6) events that jeopardized the health of the subject or required surgical intervention.
2. Non-Serious Adverse Events [ Time Frame: 1 year ]
   Non-serious adverse events include all other adverse events recorded during the study which were determined to be related or possibly related to the device, surgery, or research. It does not include adverse events that were determined to be serious, as previously defined. Safety events that were determined to be unrelated to the study were not included in this analysis.
3. Unanticipated Adverse Device Effects (UADE) [ Time Frame: 1 year ]
   Unanticipated adverse device effects (UADEs) are defined as adverse events which were determined to be serious, unexpected and related or possibly related to the investigational device.

Secondary Outcome Measures :

1. Apnea-hypopnea Index (AHI) [ Time Frame: 1 year ]
   The apnea-hypopnea index (AHI) is a measure of the number of times per hour that an apnea or hypopnea event occurs during sleep. Apneas are defined as short pauses in breathing, while hypopnea is defined as shallow breathing. The AHI is useful in evaluating obstructive sleep apnea (OSA). The normal pediatric range is typically defined as an AHI of less than 1 event per hour. An AHI between 5 and 10 events per hour is consistent with moderate OSA, while an AHI above 10 suggests severe OSA. We report the mean AHI measured 1 year after device implantation. We also report the mean change in AHI, which compares AHI from baseline to 1 year postoperatively; therefore, negative change scores indicate a decrease from baseline to 1 year.
2. Obstructive Apnea-hypopnea Index [ Time Frame: 1 year ]
   The obstructive apnea-hypopnea index is similar to the standard AHI measure, but it only includes apnea or hypopnea events that are attributable to airway obstruction, as opposed to an origin in the central nervous system (referred to as "central sleep apnea"). This value reflects the numbers of times per hour the subject experienced an obstruction-related apnea or hypopnea event during sleep. We report the mean obstructive AHI measured 1 year after device implantation. We also report the mean change in obstructive AHI, which compares obstructive AHI from baseline to 1 year postoperatively; therefore, negative change scores indicate a decrease from baseline to 1 year.
3. Central Apnea Index [ Time Frame: 1 year ]
   The central apnea-hypopnea index is similar to the standard AHI measure, but it only includes apnea or hypopnea events that arise from the central nervous system. Central apnea and hypopnea events are not caused by airway obstruction. This value reflects the numbers of times per hour the subject experienced a neurologically-related apnea or hypopnea event during sleep. We report the mean central apnea index measured 1 year after device implantation. We also report the mean change in central apnea index, which compares central apnea index from baseline to 1 year postoperatively; therefore, negative change scores indicate a decrease from baseline to 1 year.
4. Hypopnea Percentage [ Time Frame: 1 year ]
   The hypopnea percentage describes the relative frequency of hypopnea events versus apnea events. Hypopnea is defined as shallow breathing, while apnea is defined as short pauses in breathing. The hypopnea percentage reflects what percentage of the total AHI can be attributed to hypopneas as opposed to apneas during sleep. We report the mean hypopnea percentage measured 1 year after device implantation. We also report the mean change in hypopnea percentage, which compares hypopnea percentage from baseline to 1 year postoperatively; therefore, negative change scores indicate a decrease from baseline to 1 year.
5. Oxygenation Percentage of Time SpO2 < 90% [ Time Frame: 1 year ]
   During the overnight sleep studies, subjects' blood oxygen saturation (SpO2) were continuously monitored. This value reflects the percentage of their entire sleep time that the participants' blood oxygen saturation was below 90%. We report the mean percentage of time SpO2 < 90% measured 1 year after device implantation. We also report the mean change in this time, which compares percentage of time from baseline to 1 year postoperatively; therefore, negative change scores indicate a decrease from baseline to 1 year.
6. Percentage of Time ETCO2 > 50 mmHg [ Time Frame: 1 year ]
   End Tidal CO2 (ETCO2) is a measure of the carbon dioxide that is released at the end of a breath. Higher-than-normal end tidal CO2 measurements may be indicative of hypoventilation. We report here the percentage of time during sleep that subjects' end tidal CO2 exceeded the typical range of 50 mmHg. We report the mean percentage of time measured 1 year after device implantation. We also report the mean change in percentage of time ETCO2 > 50 mmHg, which compares percentage of time from baseline to 1 year postoperatively; therefore, negative change scores indicate a decrease from baseline to 1 year.
7. SpO2 Nadir [ Time Frame: 1 year ]
   The SpO2 nadir is the lowest blood oxygen saturation measurement taken throughout the sleep study. Change in SpO2 Nadir is defined from baseline to 1 year postoperatively; therefore, negative change scores indicate a decrease over time.
8. Sleep Efficiency [ Time Frame: 1 year ]
   Sleep efficiency is a measure of how much time that is dedicated to sleep is actually spent sleeping. Sleep efficiency is proportional to the amount of time spent asleep divided by the amount of time dedicated to sleep. Change in sleep efficiency is defined from baseline to 1 year postoperatively; therefore, negative change scores indicate a decrease over time.
9. REM Percentage [ Time Frame: 1 year ]
   REM percentage is the percentage of sleep time that the participant spent in the rapid eye movement (REM) phase of sleep. Change in REM percentage is defined from baseline to 1 year postoperatively; therefore, negative change scores indicate a decrease over time.
10. Arousal Index [ Time Frame: 1 year ]
    The arousal index measures the number of times per hour that the participant awoke from sleep. Change in arousal index is defined from baseline to 1 year postoperatively; therefore, negative change scores indicate a decrease over time.
11. OSA-18 Total Survey Score [ Time Frame: 1 year ]
    The OSA-18 generates from participant responses a total score between 18 and 126 which is designed to reflect the impact of obstructive sleep apnea on the pediatric patient's quality of life. Higher total scores on the OSA-18 indicate a greater, negative impact on quality of life; while lower scores indicate a lesser impact on quality of life. Interpretation of total scores is as follows: minimal OSA impact for scores under 60; moderate OSA impact for scores between 60 and 80; and severe OSA impact for scores above 80. Change in OSA-18 total survey score is defined from baseline to 1 year postoperatively; therefore, negative change scores indicate a decrease of symptom severity over time.
12. OSA-18 Overall Quality of Life Score [ Time Frame: 1 year ]
    The OSA-18 questionnaire includes a stand-alone question that asks to rate the child's overall quality of life on a scale from 0 (indicating worst quality of life possible) to 10 (indicating best quality of life possible). Change in OSA-18 overall score is defined from baseline to 1 year postoperatively; therefore, positive change scores indicate an improvement in quality of life over time.
13. Epworth Sleepiness Scale (ESS) Survey Score [ Time Frame: 1 year ]
    The ESS is a validated survey of daytime sleepiness. The ESS is scored as the sum of all items with scores ranging from 0 to 24 and higher scores indicating worse symptoms. Change ESS survey score is defined from baseline to 1 year postoperatively; therefore, negative change scores indicate an improvement in symptom severity over time.

Eligibility Criteria

• Ages Eligible for Study: 10 Years to 21 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Only children and young adults with Down Syndrome age 10-21 years with prior adenotonsillectomy will be considered for the study.
• Subjects must have BMI <95th percentile for age
• All subjects must have 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.
• 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.
• 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.
• 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.
• 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 order to participate, subjects will require written consent from both parents. All study subjects must provide written assent as well.

Exclusion Criteria:

• Subjects will be excluded if they meet the following criteria: BMI >95th percentile for age, apnea hypopnea index (AHI) <10 or >50 on in-lab polysomnography (PSG), central or mixed apneas accounting for >25% of the total AHI, 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), other medical conditions resulting in medical instability (e.g. congestive heart failure, recent open heart surgery, immunosuppression, or chronic lung disease or aspiration), presence of another medical condition requiring future magnetic resonance imaging (MRI), history of cholesteatoma, or patients with another implantable device which could interact unintentionally with the Inspire system.
• Subjects in whom general anesthesia for a surgical procedure is contraindicated due to other medical illnesses or conditions will be excluded.
• Subjects with a life expectancy < 12 months will be excluded.
• Subjects who are unable to communicate pain or discomfort to their caretaker/parent, based on parental or investigator assessment, will be excluded.
• Subjects with a history of bleeding or clotting disorders and those on blood thinning or NSAID medications will be excluded from participation.
• Subjects taking muscle relaxant medication will be excluded from participation.
• Female subjects who are pregnant or plan to become pregnant during the study period will be excluded. All female subjects 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.
• Subjects deemed unfit for participation by investigators or any other reason will be excluded.

Contacts and Locations

Locations

United States, Georgia

Children's Healthcare of Atlanta - Egleston Hospital

Atlanta, Georgia, United States, 30329

United States, Massachusetts

Massachusetts Eye and Ear

Boston, Massachusetts, United States, 02115

United States, Ohio

Cincinnati Children's Hospital

Cincinnati, Ohio, United States, 45229

United States, Pennsylvania

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15224

United States, Virginia

Children's Hospital of The King's Daughters

Norfolk, Virginia, United States, 23507

Sponsors and Collaborators

Christopher Hartnick, M.D.

Emory University

Children's Hospital Medical Center, Cincinnati

Inspire Medical Systems, Inc.

University of Pittsburgh

Children's Hospital of The King's Daughters

Investigators

• Principal Investigator: Christopher J Hartnick, MD; Massachusetts Eye and Ear

  Study Documents (Full-Text)

Documents provided by Christopher Hartnick, M.D., Massachusetts Eye and Ear Infirmary:

Study Protocol  [PDF] May 8, 2020

Informed Consent Form  [PDF] November 8, 2019

No Statistical Analysis Plan (SAP) exists for this study.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Yu PK, Stenerson M, Ishman SL, Shott SR, Raol N, Soose RJ, Tobey A, Baldassari C, Dedhia RC, Pulsifer MB, Grieco JA, Abbeduto LJ, Kinane TB, Keamy DG Jr, Skotko BG, Hartnick CJ. Evaluation of Upper Airway Stimulation for Adolescents With Down Syndrome and Obstructive Sleep Apnea. JAMA Otolaryngol Head Neck Surg. 2022 Jun 1;148(6):522-528. doi: 10.1001/jamaoto.2022.0455.

Stenerson ME, Yu PK, Kinane TB, Skotko BG, Hartnick CJ. Long-term stability of hypoglossal nerve stimulation for the treatment of obstructive sleep apnea in children with Down syndrome. Int J Pediatr Otorhinolaryngol. 2021 Oct;149:110868. doi: 10.1016/j.ijporl.2021.110868. Epub 2021 Aug 5.

Jayawardena ADL, Randolph GW, Hartnick CJ. Pediatric Modifications to Hypoglossal Nerve Stimulation for Obstructive Sleep Apnea: How I Do It. Laryngoscope. 2021 Feb;131(2):423-424. doi: 10.1002/lary.28661. Epub 2020 Apr 9. No abstract available.

Caloway CL, Diercks GR, Keamy D, de Guzman V, Soose R, Raol N, Shott SR, Ishman SL, Hartnick CJ. Update on hypoglossal nerve stimulation in children with down syndrome and obstructive sleep apnea. Laryngoscope. 2020 Apr;130(4):E263-E267. doi: 10.1002/lary.28138. Epub 2019 Jun 20.

Diercks GR, Wentland C, Keamy D, Kinane TB, Skotko B, de Guzman V, Grealish E, Dobrowski J, Soose R, Hartnick CJ. Hypoglossal Nerve Stimulation in Adolescents With Down Syndrome and Obstructive Sleep Apnea. JAMA Otolaryngol Head Neck Surg. 2018 Jan 1;144(1):37-42. doi: 10.1001/jamaoto.2017.1871.

Diercks GR, Keamy D, Kinane TB, Skotko B, Schwartz A, Grealish E, Dobrowski J, Soose R, Hartnick CJ. Hypoglossal Nerve Stimulator Implantation in an Adolescent With Down Syndrome and Sleep Apnea. Pediatrics. 2016 May;137(5):e20153663. doi: 10.1542/peds.2015-3663.

• Responsible Party: Christopher Hartnick, M.D., Principal Investigator, Massachusetts Eye and Ear Infirmary
• ClinicalTrials.gov Identifier: NCT02344108
• Other Study ID Numbers: 14-146H; 2019P001786 ( Other Identifier: Partners Human Research Committee )
• First Posted: January 22, 2015
• Results First Posted: February 11, 2022
• Last Update Posted: April 12, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes

Additional relevant MeSH terms:

Apnea; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Down Syndrome; Syndrome; Disease; Pathologic Processes; Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Abnormalities, Multiple; Congenital Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn