Hypoglossal Nerve Stimulation on Cardiovascular Outcomes (CARDIOSA-12)

Cardiovascular Endpoints for Obstructive Sleep Apnea With Twelfth Nerve Stimulation (CARDIOSA-12): A Randomized, Sham-Controlled, Double-Blind, Crossover Trial

A new, well-tolerated treatment for obstructive sleep apnea - tongue stimulation - is a device which opens the airway during sleep and can provide treatment for patients unable to use the mask and hose treatment. The study will evaluate the effect of this new treatment on blood pressure and heart-related measures to see if it lowers patients' risk of heart problems.

Study Overview

• Status: Completed
• Conditions: Obstructive Sleep Apnea
• Intervention / Treatment: Device: Therapeutic HGNS; Device: Subtherapeutic 'Sham' HGNS

Detailed Description

Obstructive sleep apnea, repetitive airway blockage during sleep, affects 1 in 10 Americans. If left untreated, it results in decreased quality of life and increased risk of heart problems. Only half of these people are able to use the main treatment, continuous positive airway pressure (CPAP) therapy, which involves wearing a mask and hose at night. A new, well-tolerated treatment - tongue stimulation - is a device which opens the airway during sleep and can provide treatment for patients unable to use the mask and hose treatment. The study will evaluate the effect of this new treatment on blood pressure and heart-related measures to see if it lowers patients' risk of heart problems.

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 22 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

All patients recruited into the study will have already been implanted with the Inspire® HGNS device.

Additional Inclusion Criteria include:

• As tolerating the therapeutic level during sleep can take time (weeks to months), all patients must be able to use the device at the therapeutic setting (> 20 hours/week for > 1 month) prior to enrollment, based on compliance data.
• All patients will be English-speaking and able to give written informed consent.

Exclusion Criteria include:

• Inspire® remote Model 2500 or later is required. Patients with older remotes are not candidates due to limited adherence monitoring capabilities.
• Patients who have fallen asleep while driving resulting in accident or "near miss" accident within 1 year prior to HGNS implantation.
• Actively using positive airway pressure (PAP) therapy for treatment of OSA.
• Patients in whom the difference between sham and therapeutic voltages is less than 30% the therapeutic voltage.

• Pregnant women will be excluded.*

  • Women of childbearing potential must NOT be pregnant or plan on becoming pregnant. This study involves temporarily stopping treatment of obstructive sleep apnea, which may harm the fetus. If applicable, the patient will need to take a urine pregnancy test after enrollment (prior to washout #1), and again prior to washout #2.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Therapeutic HGNS; Therapeutic Hypoglossal Nerve Stimulation (HGNS). Prior to enrollment in this study, the HGNS will have been implanted as part of clinical care, and a therapeutic voltage setting will have been determined via overnight sleep study.	Device: Therapeutic HGNS; Prior to enrollment in this study, the HGNS will have been implanted as part of clinical care, and a therapeutic voltage setting will have been determined via overnight sleep study The pulse generator, using technology from cardiac pacemakers, utilizes the signal from the pressure sensor for timing of stimulation to the tongue nerve. Patient will undergo activation of the implanted device one month post-operatively. A functional threshold (in volts) is obtained based on tongue motion during device stimulation. For the next month, the patient will have steadily increased stimulation strength by 0.1V every 2-3 nights within the preset range until the upper limit is reached.; Other Names: Hypoglossal Nerve Stimulation
Sham Comparator: Subtherapeutic 'Sham' HGNS; Sham threshold determination will be performed as follows. The patient will be in a reclined position with the mouth open while nasal breathing. Stimulation will be increased from 0.1V up by 0.1V until bulk tongue motion is detected without obvious protrusion. This process is repeated twice and the average value is used to determine "sham-HGNS". The electrode configuration will remain consistent between the patient's therapeutic and sham thresholds.	Device: Subtherapeutic 'Sham' HGNS; Sham threshold determination will be performed as follows. The patient will be in a reclined position with the mouth open while nasal breathing. Stimulation will be increased from 0.1V up by 0.1V until bulk tongue motion is detected without obvious protrusion. This process is repeated twice and the average value is used to determine "sham-HGNS". The electrode configuration will remain consistent between the patient's therapeutic and sham thresholds; Other Names: Sham Hypoglossal Nerve Stimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean 24-Hour Systolic Ambulatory Blood Pressure Values	Patients will undergo 24-hour ambulatory blood pressure testing (ABP) using a noninvasive, portable device. The monitor is programmed to record blood pressure every 30 minutes. The patient will be asked to record bedtime and wake time to corroborate the sleep and wake time from the recorder. Mean 24-hour systolic ambulatory blood pressure values will be calculated.	Study Week 6, Day 1; study Week 11, Day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean 24-Hour Diastolic Ambulatory Blood Pressure Values	Patients will undergo 24-hour ambulatory blood pressure testing (ABP) using a noninvasive, portable device. The monitor is programmed to record blood pressure every 30 minutes. The patient will be asked to record bedtime and wake time to corroborate the sleep and wake time from the recorder. Mean 24-hour diastolic ambulatory blood pressure values will be calculated.	Study Week 6, Day 1; study Week 11, Day 1
Mean Nocturnal Systolic and Diastolic Ambulatory Blood Pressure Values	Patients will undergo ambulatory blood pressure testing (ABP) using a noninvasive, portable device. The patient will be asked to record bedtime and wake time to corroborate the sleep and wake time from the recorder. Mean sleep systolic and diastolic ambulatory blood pressure values will be calculated.	Study Week 6, Day 1; study Week 11, Day 1
Mean Muscle Sympathetic Nerve Activity (MSNA) Frequency (Bursts/Minute)	The peroneal nerve will be located with transcutaneous stimulation and a tungsten microelectrode will be inserted into the nerve, and a reference electrode will be inserted 1-2 cm from the recording electrode. Nerve signals will be preamplified, amplified, filtered, rectified, and integrated to obtain a mean voltage display of sympathetic nerve activity that is recorded. Muscle sympathetic bursts will be identified by visual inspection and expressed as burst frequency (bursts per minute). MSNA was only performed on 7 patients at Emory University, prior to the trial being transferred to the University of Pennsylvania. This is due to there being no research collaborators available at the University of Pennsylvania to capture MSNA as part of this trial. There is insufficient data gathered to make meaningful claims regarding this outcome measure.	Study Week 6, Day 2; Study Week 11, Day 2
Mean Muscle Sympathetic Nerve Activity (MSNA) Tonal Activity (Units/Minute)	The peroneal nerve will be located with transcutaneous stimulation and a tungsten microelectrode will be inserted into the nerve, and a reference electrode will be inserted 1-2 cm from the recording electrode. Nerve signals will be preamplified, amplified, filtered, rectified, and integrated to obtain tonal activity (units/minute). MSNA was only performed on 7 patients at Emory University, prior to the trial being transferred to the University of Pennsylvania. This is due to there being no research collaborators available at the University of Pennsylvania to capture MSNA as part of this trial. There is insufficient data gathered to make meaningful claims regarding this outcome measure.	Study Week 6, Day 2; Study Week 11, Day 2
Mean Pre-Ejection Period (PEP)	A patient will be fitted with Impedance Cardiography (ICG) Noninvasive Cardiac Output Module that will record the ECG (Electrocardiogram) and the ICG (Impedance cardiography) continuously during a 10-minute period. PEP will be calculated as the average interval (milliseconds) from the onset of left ventricular depolarization, reflected by the Q-wave onset in the ECG to the opening of the aortic valve, reflected by the B-point in the ICG signal. A significant difference in PEP to be a 10 millisecond increase from baseline.	Study Week 6, Day 2; Study Week 11, Day 2
Mean Flow-mediated Dilation (FMD)	The brachial artery of the nondominant arm will be imaged using a high-resolution ultrasound transducer. A blood pressure cuff on the forearm will be inflated to suprasystolic pressures to produce 5 min of ischemia. On cuff deflation, imaging will be performed to measure FMD. Brachial artery FMD will be calculated as (post-ischemia diameter - baseline diameter) / (baseline diameter) x 100.	Study Week 6, Day 2; Study Week 11, Day 2
Mean Peripheral Arterial Stiffness (PAS)	Following a rest period of 10 minutes with subjects in a supine position in a quiet, temperature-controlled room, blood pressure will be measured 3 times at 5-minute intervals by an automatic device. The standard metric of peripheral arterial stiffness (PAS) is carotid-femoral pulse wave velocity (PWV), which will be estimated using the Sphygmocor device® (Atcor Medical, Sydney, Australia). PAS was only captured on 21 patients at Emory University and the University of Pennsylvania. This is due to our cardiovascular research collaborators at the University of Pennsylvania indicating they would no longer be able to support our research study due to their own COVID-19 related resource constraints. There is insufficient data gathered to make meaningful claims regarding this outcome measure. PAS is reported as changes in pulse wave velocity, with a meters/second unit measure.	Study Week 6, Day 2; Study Week 11, Day 2
Mean Psychomotor Vigilance Test (PVT) Reciprocal Reaction Time	Patients will perform the neurobehavioral test on a specially calibrated (for timing precision) and designated laptop in a quiet room in the outpatient setting. Each patient will perform a unique version of the psychomotor vigilance test to assess psychomotor speed. The trial's protocol was amended to begin capturing neurobehavioral measures like the PVT at the University of Pennsylvania, as part of a new collaboration with research collaborators in the Department of Psychiatry. PVT is a validated instrument to capture attention, and response time on this cognitive test is reported as reciprocal milliseconds or 1/milliseconds.	Study Week 6, Day 2; Study Week 11, Day 2
Mean Digit Symbol Substitution Test (DSST) Reaction Time	Patients will perform the neurobehavioral test on a specially calibrated (for timing precision) and designated laptop in a quiet room in the outpatient setting. Each patient will perform a unique version of the digit symbol substitution test to assess processing speed. The trial's protocol was amended to begin capturing neurobehavioral measures like the DSST at the University of Pennsylvania, as part of a new collaboration with research collaborators in the Department of Psychiatry. DSST is a validated instrument to capture visual tracking and working memory, and response time on this cognitive test is reported in milliseconds.	Study Week 6, Day 2; Study Week 11, Day 2

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: American Heart Association; American Academy of Sleep Medicine

Publications and helpful links

General Publications

• Dedhia RC, Quyyumi AA, Park J, Shah AJ, Strollo PJ, Bliwise DL. Cardiovascular endpoints for obstructive sleep apnea with twelfth cranial nerve stimulation (CARDIOSA-12): Rationale and methods. Laryngoscope. 2018 Nov;128(11):2635-2643. doi: 10.1002/lary.27284. Epub 2018 Sep 8.

Study record dates

Study Major Dates

• Study Start (Actual): December 13, 2017
• Primary Completion (Actual): January 21, 2022
• Study Completion (Actual): January 21, 2022

Study Registration Dates

• First Submitted: November 27, 2017
• First Submitted That Met QC Criteria: November 30, 2017
• First Posted (Actual): December 2, 2017

Study Record Updates

• Last Update Posted (Actual): March 30, 2023
• Last Update Submitted That Met QC Criteria: March 29, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Cardiovascular function; Sleep apnea; Tongue stimulation
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Signs and Symptoms, Respiratory; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Apnea
• Other Study ID Numbers: 834158

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No