Respicardia, Inc. Pivotal Trial of the remedē System

Study Overview
=================
Brief Summary
-----------------
The primary purpose of this prospective, multicenter, randomized trial is to evaluate the safety and effectiveness of therapy delivered by the remedē® system in subjects with moderate to severe central sleep apnea and optimal medical management, compared to outcomes in randomized control subjects receiving optimal medical management and implanted but inactive remedē® systems.

Official Title
-----------------
A Randomized Trial Evaluating the Safety and Effectiveness of the remedē® System in Patients With Central Sleep Apnea

Conditions
-----------------
Sleep Apnea, Central, Sleep Disordered Breathing, Heart Failure

Intervention / Treatment
-----------------
* Device: Treatment Group (transvenous stimulation of the phrenic nerve)
* Device: Control Group (Optimal Medical Therapy)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: At least 18 years of age Central Sleep apnea confirmed by core lab analysis of PSG with EEG within 40 days of scheduled implant: Apnea/Hypopnea Index (AHI) greater than or equal to 20; Central Apnea Index (CAI) at least 50% of all apneas, with at least 30 central apnea events; Oxygen Desaturation Index (OAI) less than or equal to 20% of the total AHI Medically stable for 30 days prior to all baseline testing (including PSG), i.e., no hospitalizations for illness, no breathing mask-based therapy, and on stable medications and therapies: Stable medications are defined as no changes during this period except for those within a pre-specified sliding scale medication regimen; If the subject has heart failure, the baseline testing (including PSG) should occur at least 6 months after initial diagnosis; If the subject has systolic heart failure, the baseline testing (including PSG) should occur after maximally titrating beta blockers, angiotensin converting enzyme inhibitors (ACE-I) and other medications indicated in the current guidelines (unless contraindicated or not considered medically necessary) and after receiving any indicated device therapy including devices for cardiac resynchronization therapy and/or primary prevention of sudden cardiac death; If subject has a hospitalization or physician visit requiring IV medication between the screening PSG and implant, the subject must be re-screened when stable Expected to tolerate study procedures in the opinion of the investigator, in particular: Ability to lie down long enough to insert the remede system without shortness of breath and able to tolerate instrumentation for the Polysomnogram/Polygram testing; Expected to tolerate therapy titration and the sensation of therapy, and communicate therapy experience. In the investigator's opinion, willing and able to comply with all study requirements Signed the Institutional Review Board/Medical Ethics Committee approved informed consent (HIPAA authorization in the U.S.) Exclusion Criteria: Pacemaker dependent subjects without any physiologic escape rhythm Suspected inability to place catheter for delivery of stimulation lead (e.g. previously know coagulopathy, distorted anatomy, prior failed pectoral implant, etc.) Evidence of phrenic nerve palsy More than 2 previous open chest surgical procedures (e.g., CABG) Etiology of central sleep apnea known to be caused primarily by pain medication Documented history of psychosis or severe bipolar disorder Cerebrovascular accident (CVA) within 12 months of baseline testing History of idiopathic pulmonary hypertension, World Health Organization Class 1 Limited pulmonary function with either forced expiratory volume (FEV) 1/forced vital capacity (FVC) less than 65% of predicted value or FVC less than 60% of predicted value Baseline oxygen saturation less than 92% while awake and on room air after 5 minutes of quiet rest Anticipated need for chronic oxygen therapy or breathing mask-based therapy for 6 months post therapy initiation visit Active infection or sepsis within 30 days of enrollment Currently on renal dialysis or creatinine level greater than 2.5 mg/dL or calculated creatinine clearance equal to or less than 30 ml/min using the Cockcroft-Gault equation Poor liver function with baseline aspartate transaminase (AST), alanine transaminase (ALT), and/or total bilirubin greater than 3 times the upper limit of normal (per lab normals at each site) Hemoglobin less than 8 gm/dL In subjects with heart failure, American College of Cardiology (ACC)/American Heart Association Heart (AHA) Stage D Within the 3 months prior to baseline testing, any of the following: uncorrected severe valvular stenosis, valve replacement or repair (percutaneous or surgical), myocardial infarction (MI), coronary artery bypass grafting (CABG) surgery, percutaneous coronary intervention (PCI), cardiac ablation, new cardiac resynchronization device or new pacemaker implant New implantable cardioverter defibrillator or any implantable device generator change-out within 30 days prior to baseline testing or anticipated within the first 6 months of enrollment Other anticipated surgery or invasive procedure expected to affect ability to perform testing at 6-month post-therapy initiation visit Unstable angina Allergy to or intolerant of contrast dye Pregnancy or of child bearing potential without a negative pregnancy test within 10 days prior to remede system implant Life expectancy or expected time to transplant or left ventricular assist device of less than 12 months Currently enrolled or planning to enroll in another study that may conflict with protocol requirements or confound subject results in this trial

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

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Group<br>Subjects implanted with the remedē system device and randomized to the Treatment group will receive optimal medical therapy and have the remedē system initiated to deliver transvenous stimulation of the phrenic nerve at the Therapy Initiation Visit (1 month post device implant). | Device: Treatment Group (transvenous stimulation of the phrenic nerve)<br>* device implant, optimal medical therapy and device initiation 1 month post implant.<br>* Other names: Transvenous stimulation of the phrenic nerve;|
| Other: Control group<br>Subjects implanted with the remedē system device and randomized to the Control group will receive optimal medical therapy through the 6-month Post-Therapy Initiation Visit. Control group subjects will have the remedē system initiated to deliver transvenous stimulation of the phrenic nerve at the 6-month Post-Therapy Initiation Visit (7 months post device implant). | Device: Control Group (Optimal Medical Therapy)<br>* device implant, optimal medical therapy and delayed device initiation (7 months post device implant)<br>* Other names: Optimal Medical Therapy;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Proportion of Participants Experiencing a Reduction in Apnea-hypopnea Index (AHI) | Comparison of the proportion of subjects in the Treatment group achieving a 50% or greater reduction in AHI from baseline to 6 months compared to the Control group. | 6 months | 
| Freedom From Related Serious Adverse Events Within 12 Months | Freedom from serious adverse events (SAEs) associated with the implant procedure, the remede System, or the delivered therapy at 12 months post therapy initiation visit. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Central Apnea Index (CAI) Change From Baseline at 6 Months | Change in CAI = Month 6 index - Baseline index. The central apnea index is a measurement used to indicate the severity of central sleep apnea. It is represented by the number of central apnea events per hour of sleep. | 6 months | 
| Apnea-Hypopnea Index (AHI) Change From Baseline at 6 Months | Change in AHI = Month 6 index - Baseline index. The Apnea-Hypopnea Index is a measurement used to indicate the severity of sleep apnea. It is represented by the number of apnea and hypopnea events per hour of sleep. | 6 months | 
| Arousal Index (ArI) Change From Baseline at 6 Months | Change in ArI = Month 6 index - Baseline index. The Arousal Index is a measurement used to indicate the number of times per hour of sleep that sleep is disrupted. | 6 months | 
| Rapid Eye Movement (REM) Sleep Change From Baseline at 6 Months | Change in REM = Month 6 percentage - Baseline percentage. Rapid Eye Movement (REM) is a sleep stage. A higher percentage of sleep in REM is a measure of better sleep quality. | 6 months | 
| The Proportion of Participants Experiencing a Marked or Moderate Improvement in Patient Global Assessment at 6 Months | The proportion of subjects with a moderate or marked improvement in the Patient Global Assessment from baseline to the 6 month visit | 6 months | 
| Oxygen Desaturation Index 4% (ODI4) Change From Baseline at 6 Months | Change in ODI4 = Month 6 index - Baseline index. The Oxygen Desaturation Index 4% is a measurement of the number of times per hour of sleep that the blood's oxygen level drops ≥4%. | 6 months | 
| Epworth Sleepiness Scale (ESS) Change From Baseline at 6 Months | Change in ESS = Month 6 score - Baseline score. The ESS is an assessment to measure a subject's general level of daytime sleepiness. Scores can range from 0-24, with higher scores indicating higher level of daytime sleepiness. | 6 months |