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HGNS on Cardiovascular Outcomes

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ClinicalTrials.gov Identifier: NCT03359096
Recruitment Status : Recruiting
First Posted : December 2, 2017
Last Update Posted : July 30, 2020
Sponsor:
Collaborators:
American Heart Association
American Academy of Sleep Medicine
Information provided by (Responsible Party):
Raj Dedhia, MD, University of Pennsylvania

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Obstructive Sleep Apnea Device: Therapeutic HGNS Device: Subtherapeutic 'Sham' HGNS Not Applicable

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 (CPAP) 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Washout Period 1 (Study Week 1): The patient will not use Hypoglossal Nerve Stimulation (HGNS) for 1 week. Randomization Visit (Study Week 2): The patient will be randomized to sub-therapeutic HGNS (sham) or therapeutic HGNS (treatment) for 28 days. Sympathetic and Vascular testing (Study Week 6). Washout Period 2 (Study Week 6-7): The patient will not use HGNS for 7 days. The patient will be switched to the other intervention arm (treatment to sham vs. sham to treatment) for 28 days.Sympathetic and Vascular testing (Study Week 11).
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Cardiovascular Endpoints for Obstructive Sleep Apnea With Twelfth Nerve Stimulation (CARDIOSA-12): A Randomized, Sham-Controlled, Double-Blinded, Crossover Trial
Actual Study Start Date : December 13, 2017
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Sleep Apnea

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 Name: 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 Name: Sham Hypoglossal Nerve Stimulation




Primary Outcome Measures :
  1. Change in mean 24-HOUR systolic ambulatory blood pressure values [ Time Frame: Study Week 6, Day 1; study Week 11, Day 1 ]
    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.


Secondary Outcome Measures :
  1. Change in mean 24-HOUR diastolic ambulatory blood pressure values [ Time Frame: Study Week 6, Day 1; study Week 11, Day 1 ]
    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.

  2. Change in mean SLEEP systolic and diastolic ambulatory blood pressure values [ Time Frame: Study Week 6, Day 1; study Week 11, Day 1 ]
    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.

  3. Change in Muscle Sympathetic Nerve Activity (MSNA) frequency (bursts/minute) [ Time Frame: Study Week 6, Day 2; Study Week 11, Day 2 ]
    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).

  4. Change in Muscle Sympathetic Nerve Activity (MSNA) ) tonal activity (units/minute) [ Time Frame: Study Week 6, Day 2; Study Week 11, Day 2 ]
    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).

  5. Change in Pre-Ejection Period (PEP) duration [ Time Frame: Study Week 6, Day 2; Study Week 11, Day 2 ]
    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.

  6. Change in Flow-mediated dilation (FMD) [ Time Frame: Study Week 6, Day 2; Study Week 11, Day 2 ]
    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.

  7. Change in Peripheral arterial stiffness (PAS) [ Time Frame: Study Week 6, Day 2; Study Week 11, Day 2 ]
    Following a rest period of 10 minutes with subjects in a supine position, blood pressure will be measured 3 times at 5-min intervals by an automatic device. Peripheral arterial stiffness will be estimated using Sphygmocor device.

  8. Change in Pulse Wave Velocity (PWV) [ Time Frame: Study Week 6, Day 2; Study Week 11, Day 2 ]
    Following a rest period of 10 minutes with subjects in a supine position in a quiet, temperature-controlled room, the Sphygmocor device® (Atcor Medical, Sydney, Australia) will measure Pulse wave velocity (PWV).

  9. Change in Psychomotor Vigilance Test (PVT) score [ Time Frame: Study Week 6, Day 2; Study Week 11, Day 2 ]
    The patient will perform neurobehavioral tests on a designated laptop in a quiet room at the Otorhinolaryngology clinic. Each subject will perform a unique version of the psychomotor vigilance test. The laptop is calibrated for timing precision.

  10. Change in Digit Symbol Substitution Test (DSST) score [ Time Frame: Study Week 6, Day 2; Study Week 11, Day 2 ]
    The patient will perform neurobehavioral tests on a designated laptop in a quiet room at the Otorhinolaryngology clinic. Each subject will perform a unique version of the digit symbol substitution test. The laptop is calibrated for timing precision.



Information from the National Library of Medicine

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Ages Eligible for Study:   22 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Eligibility Criteria: Similar to criteria put forth by the Federal Drug Administration (FDA), HGNS Implantation Inclusion Criteria include:

  • Apnea-Hypopnea Index (AHI) of 15-65 with <25% central apneas on recent sleep testing.
  • Not able to use PAP > 4 hours for 5 nights/week -OR- unwilling to use PAP.
  • No circumferential collapse at velopharynx on drug-induced sedated endoscopy.
  • 22 years of age or older.
  • 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 have a pre-operative sleep study (baseline), 2-month in-lab sleep study (titration), and if applicable, a post-HGNS sleep study (efficacy) available for review.
  • 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.
  • Pregnant women will be excluded.*
  • 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.
  • * Women of child bearing 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03359096


Contacts
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Contact: Akshay Tangutur, MS 215-615-8777 akshay.tangutur@pennmedicine.upenn.edu
Contact: Everett Seay everett.seay@pennmedicine.upenn.edu

Locations
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United States, Pennsylvania
Hospital of the University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Raj C Dedhia, MD, MS    215-349-5009    raj.dedhia@pennmedicine.upenn.edu   
Contact: Elizabeth Beothy    215-614-0036    eabeothy@pennmedicine.upenn.edu   
Principal Investigator: Raj C Dedhia, MD, MS         
Sub-Investigator: Erica Thaler, MD         
Sponsors and Collaborators
University of Pennsylvania
American Heart Association
American Academy of Sleep Medicine
Investigators
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Principal Investigator: Raj C Dedhia, MD, MS University of Pennsylvania
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Responsible Party: Raj Dedhia, MD, Associate Professor of Otorhinolaryngology: Head and Neck Surgery, University of Pennsylvania
ClinicalTrials.gov Identifier: NCT03359096    
Other Study ID Numbers: 834158
First Posted: December 2, 2017    Key Record Dates
Last Update Posted: July 30, 2020
Last Verified: July 2020

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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
Keywords provided by Raj Dedhia, MD, University of Pennsylvania:
Sleep apnea
Tongue stimulation
Cardiovascular function
Additional relevant MeSH terms:
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Apnea
Sleep Apnea Syndromes
Sleep Apnea, Obstructive
Respiration Disorders
Respiratory Tract Diseases
Signs and Symptoms, Respiratory
Sleep Disorders, Intrinsic
Dyssomnias
Sleep Wake Disorders
Nervous System Diseases