Obstructive Sleep Apnea Therapy by Stimulation of the Hypoglossal Nerve

Study Overview
=================
Brief Summary
-----------------
Continuous positive airway pressure (CPAP) is the gold standard to normalize breathing during sleep in patients with obstructive sleep apnea syndrom (OSA). Many patients will not tolerate or will not accept CPAP. Implanted nerve stimulation is a novel therapy for OSA patients that restores the upper airway potency using unilateral XII nerve electric stimulation. The principal objective of this study is short-term efficacy of a new treatment for OSA on blood pressure variability during sleep.

Detailed Description
-----------------
Obstructive sleep apnea (OSA) syndrome had become over the last decade a serious health concern due to its high prevalence which raise 10% of the general population. It is characterized by recurrent episodes of airflow obstruction in the upper airway (UA) consequence of passive collapse of the UA, particularly at the tongue level. These collapses induce recurrent asphyxia that results in oxygen desaturations with persistant and crescendo respiratory efforts inducing arousals from sleep. Indeed, despite its large efficacy some of the patients will never accept continuous positive airway pressure treatment or will not tolerate. To this extent, alternative treatement has been developed: implanted hypoglossal stimulation. This treatment has been developed by Inspire Medical Device. The Inspire® system is intended to prevent base-of-tongue obstruction as well as specific soft palate obstructions by stimulating the hypoglossal nerve synchronous with respiration. A selection processus will be applied in order to identify the patients that will be good responders to the hypoglossal stimulation. The main criterion of selection is based on Drug Induced Sleep Endoscopy(DISE) that will be performed by a trained endoscopist dedicated to this study. This sleep endoscopy allows to visualize during induced sleep the shape of the UA and the type of collapsus. Indeed an antero-posterior collapsus is related to a good response to hypoglossal nerve stimulation while complete concentric obstruction at velopharyngeal is a predictor of poor response. In this pilot study, the investigators evaluate as a primary outcome the delta range of blood pressure during sleep but also other cardiovascular indexes targeting blood pressure and heart rate variability as secondary outcomes.

Official Title
-----------------
Upper AIRway Implanted Nerve STIMulation Therapy: A Breakthrough in Obstructive Sleep Apnea Therapy

Conditions
-----------------
Obstructive Sleep Apnea Syndrome

Intervention / Treatment
-----------------
* Device: Activated Inspire® Upper Airway Stimulation System
* Device: Inactivated Inspire® Upper Airway Stimulation System


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient aged 18 to 80 years old Patient with moderate to severe OSA based on an established diagnosis of OSA (15≤AHI<65) by polysomnography or respiratory polygraphy not older thant three years. Patient with moderate to severe OSA naïve of treatment or with difficulty accepting or adhering to CPAP treatment. Willing and capable to have stimulation hardware permanently implanted, and to use the patient programmer to activate the stimulation Willing and capable to return for all follow-up visits and conduct sleep studies at home, including the evaluation procedures and filling out questionnaires Willing and capable of providing written informed consent. Exclusion Criteria: Any anatomical finding that would compromise the performance of upper airway stimulation, such as the presence of complete concentric collapse of the soft palate Have any condition or procedure that has compromised neurological control of the upper airway Unable to operate the patient programmer Pregnant or plan to become pregnant, and breastfeeding women Require magnetic resonance imaging (MRI) Have an implantable device that may be susceptible to unintended interaction with the Inspire system. Additional exclusions for study purposes only Body Mass Index (BMI) of >32 Central + mixed apneas > 25% of the total apnea-hypopnea index (AHI) Neuromuscular disease Hypoglossal-nerve palsy Severe restrictive or obstructive pulmonary disease Moderate-to-severe pulmonary arterial hypertension Severe valvular heart disease New York Heart Association class III or IV heart failure Recent myocardial infarction or severe cardiac arrhythmias (within the past 6 months) Persistent uncontrolled hypertension despite medication use Coexisting nonrespiratory sleep disorders that would confound functional sleep assessment Any chronic medical illness or condition that contraindicates a surgical procedure under general anesthesia, as judged by the clinical study Investigator a terminal illness with life expectancy < 12 months Active psychiatric disease (psychotic illness, major depression, or acute anxiety attacks) which prevents subject compliance with the requirements of the investigational study testing Radiotherapy or ablation therapy of the head and/or neck Surgical resection for cancer or congenital malformations in the larynx, tongue, or throat(with exception of tonsillectomy and/or adenoidectomy) Previous surgery within 3 months performed on the soft-palate tissue Obvious fixed upper airway obstructions (tumors, polyps, unilateral nasal obstruction) Need for chronic supplemental oxygen therapy for any other reason, pO2 (partial pressure of oxygen) < 55 mm Hg Clinical evidence of severe renal failure (Stage 4 or 5) undergoing dialysis or expected to institute dialysis within 6 months Patients on medication that may alter consciousness, the pattern of respiration or sleep architecture (for example, benzodiazepiones, opiates, neuroleptics, prescription stimulants, phenothiazine, or any form of chemical substance abuse) Patients taking blood thinning medications (for example warfarin, aspirin, plavix or other blood thinning agents which cannot be safety stopped or bridged temporarily to allow surgery to take place) Any other reason for the investigator deems that the subject is unfit for participation in the study Subject in exclusion period for another study Subject under administrative or judicial control.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Monocentric, prospective, controlled, patient single-blind study
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Activated Inspire® Upper Airway Stimulation System<br>INSPIRE® device will be active a month | Device: Activated Inspire® Upper Airway Stimulation System<br>* At first, INSPIRE® device will be active a month<br>|
| Placebo Comparator: Inactivated Inspire® Upper Airway Stimulation System<br>After a period 15 days of wash-out the INSPIRE® device will be inactivated for a second period of one month. | Device: Inactivated Inspire® Upper Airway Stimulation System<br>* After 15 days wash-out INSPIRE® device will be inactivated for a second period of one month.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Short-term efficacy of a new treatment for OSA on systolic blood pressure variability during sleep | Change in the difference between delta nocturnal systolic blood pressure (difference between maximum and minimal nocturnal systolic blood pressure ; nocturnal period is defined from 10 pm to 7am). | one month treatment active versus non active treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Short-term efficacy of a new treatment for OSA on mean-24h, daytime and nighttime blood pressure | Ambulatory 24h arterial blood pressure | one month treatment active versus non active treatment | 
| Clinical efficacy of this new treatment on OSA by Epworth sleepiness scale score | It's a self-administered questionnaire with 8 questions. Patients are asked to rate, on a 4-point scale (0-3), their usual chances of dozing off or falling asleep while engaged in eight different activities. The ESS score (the sum of 8 item scores, 0-3) can range from 0 to 24. The higher the ESS score, the higher that person has daytime sleepiness. | one month treatment active versus non active treatment | 
| Clinical efficacy of this new treatment on Apnea-Hypopnea Index measured by polysomnography | Apnea-Hypopnea Index expressed in number per hour | one month treatment active versus non active treatment | 
| Change in sympatho-vagal balance based on heart rate variability analysis | ECG polysomnography | one month treatment active versus non active treatment | 
| Self-reported changes in sleep and quality of life by SF-36 score | The SF-36 is a 36-item scale constructed to survey health status and quality of life (Ware & Sherbourne, 1992), assessing eight health concepts: limitations in Quality of life physical activities because of health problems; limitations in social activities because of physical or emotional problems; limitations in usual role activities because of physical health problems); bodily pain; general mental health (psychological distress and well-being); limitations in usual role activities because of emotional problems; vitality (energy and fatigue); and general health perceptions. The standard form of the instruments asks for participants to reply to questions according to how they have felt over the previous week. The items use Likert-type scales, some with 5 or 6 points and others with 2 or 3 points. The SF-36 has been widely used and has excellent psychometrics. | one month treatment active versus non active treatment | 
| Sleep latency assessed during a Maintenance of Wakefulness Test | Mean sleep latency from the 4 sessions of the Maintenance of Wakefulness Test | one month treatment active versus non active treatment | 
| Nocturnal pulse pressure assessed by Continuous Non-invasive Arterial Pressure monitoring | Pulse pressure variability indexe DeltaBP in mmHg. | one month treatment active versus non active treatment | 
| Short-term efficacy of a new treatment for OSA on diastolic blood pressure variability during sleep | Change in the difference between delta nocturnal systolic blood pressure (difference between maximum and minimal nocturnal systolic blood pressure ; nocturnal period is defined from 10 pm to 7am). | one month treatment active versus non active treatment | 
| Clinical efficacy of this new treatment on OSA by Pichot weakness scale score | It's a self-administered questionnaire with 8 questions. Patients are asked to rate, on a 5-point scale (0-4), their usual feeling of tiredness or weakness while engaged in eight different activities. The PWS score (the sum of 8 item scores, 0-4) can range from 0 to 32. The higher the PWS score, the higher that person has weakness. | one month treatment active versus non active treatment | 
| Clinical efficacy of this new treatment on nocturia | Assessment of nocturia number by nigt | one month treatment active versus non active treatment | 
| Clinical efficacy of this new treatment on morning asthenia | Patients are asked to assess, on a visual analogic scale morning asthenia. The items use a visual analogic scales from 0 to 10 points. | one month treatment active versus non active treatment | 
| Clinical efficacy of this new treatment on morning headache | Patients are asked to assess, on a visual analogic scale morning headache. The items use a visual analogic scales from 0 to 10 points. | one month treatment active versus non active treatment | 
| Clinical efficacy of this new treatment on snoring | Patients are asked to assess, on a visual analogic scale snoring. The items use a visual analogic scales from 0 to 10 points. | one month treatment active versus non active treatment | 
| Self-reported changes in sleep and quality of life by FOSQ score | This is a disease specific quality of life questionnaire to determine functional status in adults; measures are designed to assess the impact of disorders of excessive sleepiness on multiple activities of everyday living and the extent to which these abilities are improved by effective treatment. The 5 domains that the FOSQ measures are as follows: Activity level, vigilance, intimacy and sexual relationships, general productivity, social outcome, rate the difficulty of performing a given activity on a 4-point scale (no difficulty to extreme difficulty). | one month treatment active versus non active treatment | 
| Clinical efficacy of this new treatment on oxygen desaturation index measured by polysomnography | Oxygen desaturation index expressed in number | one month treatment active versus non active treatment | 
| Clinical efficacy of this new treatment on sleep efficacy measured by polysomnography | Sleep efficacy expressed by ratio of total sleep time on total sleep period | one month treatment active versus non active treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stimulation, hypoglossal nerve, Upper-airway