Respicardia, Inc. Pivotal Trial of the remedē System

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

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Sleep Disordered Breathing; Sleep Apnea, Central
• Intervention / Treatment: Device: Treatment Group (transvenous stimulation of the phrenic nerve); Device: Control Group (Optimal Medical Therapy)

• Study Type: Interventional
• Enrollment (Actual): 151
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Germany
  • Bad Oeynhausen, Germany
    • Bad Oeynhausen- Heart & Diabetes Center
  • Berlin, Germany
    • Charite Medical School, Campus Virchow-Klinikum
  • Bernau, Germany
    • Bernau-Herzzentruym Brandenburg
  • Bielefeld, Germany
    • Bielefeld-Klinikun
  • Hamburg, Germany
    • Hamburg: Universitares Herzzentrum
  • Kassel, Germany
    • Ambulantes Herzzentrum-Kassel
• Poland
  • Wroclaw, Poland
    • Fourth Military Hospital
• United States
  • California
    • Los Angeles, California, United States, 90033
      • Keck Hospital of USC
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida - Jacksonville
  • Illinois
    • Downers Grove, Illinois, United States, 60566
      • Advocate Medical Group
    • Naperville, Illinois, United States, 60566
      • Edward Hospital-Advocate Medical Group
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland, Baltimore
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Bayview Medical Center
  • Michigan
    • Farmington Hills, Michigan, United States, 48334
      • Detroit Clinical Research Center
    • Grand Rapids, Michigan, United States, 49525
      • Spectrum Health
  • Minnesota
    • Saint Paul, Minnesota, United States, 55102
      • United Heart and Vascular (Allina)
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Mid America Heart Institute
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • Bryan Heart
  • New Jersey
    • Cherry Hill, New Jersey, United States, 08034
      • Cooper Health System
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Novant Medical Group, Inc. Presbyterian Sleep Health Charlotte
    • Winston-Salem, North Carolina, United States, 27103
      • Forsyth Medical Center - Novant
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • The Lindner Center for Research and Education at Christ Hospital
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17603
      • Lancaster General Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of University of Pennsylvania
  • Tennessee
    • Memphis, Tennessee, United States, 38138
      • Stern Cardiovascular
  • Texas
    • San Antonio, Texas, United States, 78229
      • Methodist Healthcare System
  • Virginia
    • Richmond, Virginia, United States, 23219
      • Virginia Commonwealth University
  • Wisconsin
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. At least 18 years of age

2. 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

3. 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

4. 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.
5. In the investigator's opinion, willing and able to comply with all study requirements
6. Signed the Institutional Review Board/Medical Ethics Committee approved informed consent (HIPAA authorization in the U.S.)

Exclusion Criteria:

1. Pacemaker dependent subjects without any physiologic escape rhythm
2. Suspected inability to place catheter for delivery of stimulation lead (e.g. previously know coagulopathy, distorted anatomy, prior failed pectoral implant, etc.)
3. Evidence of phrenic nerve palsy
4. More than 2 previous open chest surgical procedures (e.g., CABG)
5. Etiology of central sleep apnea known to be caused primarily by pain medication
6. Documented history of psychosis or severe bipolar disorder
7. Cerebrovascular accident (CVA) within 12 months of baseline testing
8. History of idiopathic pulmonary hypertension, World Health Organization Class 1
9. 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
10. Baseline oxygen saturation less than 92% while awake and on room air after 5 minutes of quiet rest
11. Anticipated need for chronic oxygen therapy or breathing mask-based therapy for 6 months post therapy initiation visit
12. Active infection or sepsis within 30 days of enrollment
13. 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
14. 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)
15. Hemoglobin less than 8 gm/dL
16. In subjects with heart failure, American College of Cardiology (ACC)/American Heart Association Heart (AHA) Stage D
17. 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
18. 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
19. Other anticipated surgery or invasive procedure expected to affect ability to perform testing at 6-month post-therapy initiation visit
20. Unstable angina
21. Allergy to or intolerant of contrast dye
22. Pregnancy or of child bearing potential without a negative pregnancy test within 10 days prior to remede system implant
23. Life expectancy or expected time to transplant or left ventricular assist device of less than 12 months
24. Currently enrolled or planning to enroll in another study that may conflict with protocol requirements or confound subject results in this trial

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Group; 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); device implant, optimal medical therapy and device initiation 1 month post implant.; Other Names: remedē System; Transvenous stimulation of the phrenic nerve
Other: Control group; 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); device implant, optimal medical therapy and delayed device initiation (7 months post device implant); 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

Collaborators and Investigators

• Sponsor: Respicardia, Inc.
• Investigators: Principal Investigator: Maria Rosa Costanzo, M.D., Midwest Heart Specialists

Publications and helpful links

General Publications

• Costanzo MR, Javaheri S, Ponikowski P, Oldenburg O, Augostini R, Goldberg LR, Stellbrink C, Fox H, Schwartz AR, Gupta S, McKane S, Meyer TE, Abraham WT; remede(R)System Pivotal Trial Study Group. Transvenous Phrenic Nerve Stimulation for Treatment of Central Sleep Apnea: Five-Year Safety and Efficacy Outcomes. Nat Sci Sleep. 2021 Apr 29;13:515-526. doi: 10.2147/NSS.S300713. eCollection 2021.
• Schwartz AR, Goldberg LR, McKane S, Morgenthaler TI. Transvenous phrenic nerve stimulation improves central sleep apnea, sleep quality, and quality of life regardless of prior positive airway pressure treatment. Sleep Breath. 2021 Dec;25(4):2053-2063. doi: 10.1007/s11325-021-02335-x. Epub 2021 Mar 20.
• Javaheri S, McKane S. Transvenous phrenic nerve stimulation to treat idiopathic central sleep apnea. J Clin Sleep Med. 2020 Dec 15;16(12):2099-2107. doi: 10.5664/jcsm.8802.
• Costanzo MR. Central Sleep Apnea in Patients with Heart Failure-How to Screen, How to Treat. Curr Heart Fail Rep. 2020 Oct;17(5):277-287. doi: 10.1007/s11897-020-00472-0.
• Oldenburg O, Costanzo MR, Germany R, McKane S, Meyer TE, Fox H. Improving Nocturnal Hypoxemic Burden with Transvenous Phrenic Nerve Stimulation for the Treatment of Central Sleep Apnea. J Cardiovasc Transl Res. 2021 Apr;14(2):377-385. doi: 10.1007/s12265-020-10061-0. Epub 2020 Aug 12. Erratum In: J Cardiovasc Transl Res. 2022 Jun;15(3):687.
• Fox H, Oldenburg O, Javaheri S, Ponikowski P, Augostini R, Goldberg LR, Stellbrink C, Mckane S, Meyer TE, Abraham WT, Costanzo MR. Long-term efficacy and safety of phrenic nerve stimulation for the treatment of central sleep apnea. Sleep. 2019 Oct 21;42(11):zsz158. doi: 10.1093/sleep/zsz158.
• Costanzo MR, Ponikowski P, Javaheri S, Augostini R, Goldberg L, Holcomb R, Kao A, Khayat RN, Oldenburg O, Stellbrink C, Abraham WT; remede System Pivotal Trial Study Group. Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial. Lancet. 2016 Sep 3;388(10048):974-82. doi: 10.1016/S0140-6736(16)30961-8. Epub 2016 Sep 1.
• Costanzo MR, Augostini R, Goldberg LR, Ponikowski P, Stellbrink C, Javaheri S. Design of the remede System Pivotal Trial: A Prospective, Randomized Study in the Use of Respiratory Rhythm Management to Treat Central Sleep Apnea. J Card Fail. 2015 Nov;21(11):892-902. doi: 10.1016/j.cardfail.2015.08.344.

Study record dates

Study Major Dates

• Study Start: March 1, 2013
• Primary Completion (Actual): September 10, 2016
• Study Completion (Actual): November 7, 2017

Study Registration Dates

• First Submitted: March 19, 2013
• First Submitted That Met QC Criteria: March 21, 2013
• First Posted (Estimate): March 22, 2013

Study Record Updates

• Last Update Posted (Actual): June 29, 2018
• Last Update Submitted That Met QC Criteria: May 31, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Apnea; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Sleep Apnea Syndromes; Sleep Apnea, Central
• Other Study ID Numbers: Respicardia CR-1005