Clinical trial NCT01816776: Respicardia, Inc. Pivotal Trial of the remedē System
Official title: A Randomized Trial Evaluating the Safety and Effectiveness of the remedē® System in Patients With Central Sleep Apnea
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Sleep Apnea, Central
Sleep Disordered Breathing
Heart Failure
Lead sponsor: Respicardia, Inc.
Sponsor class: INDUSTRY
First posted: 2013-03-22
Enrollment: 151
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: The Proportion of Participants Experiencing a Reduction in Apnea-hypopnea Index (AHI)
timeFrame: 6 months
measure: Freedom From Related Serious Adverse Events Within 12 Months
timeFrame: 12 months
Secondary outcomes:
measure: Central Apnea Index (CAI) Change From Baseline at 6 Months
timeFrame: 6 months
measure: Apnea-Hypopnea Index (AHI) Change From Baseline at 6 Months
timeFrame: 6 months
measure: Arousal Index (ArI) Change From Baseline at 6 Months
timeFrame: 6 months
measure: Rapid Eye Movement (REM) Sleep Change From Baseline at 6 Months
timeFrame: 6 months
measure: The Proportion of Participants Experiencing a Marked or Moderate Improvement in Patient Global Assessment at 6 Months
timeFrame: 6 months
measure: Oxygen Desaturation Index 4% (ODI4) Change From Baseline at 6 Months
timeFrame: 6 months
measure: Epworth Sleepiness Scale (ESS) Change From Baseline at 6 Months
timeFrame: 6 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Keck Hospital of USC
state: California
city: Jacksonville
country: United States
facility: University of Florida - Jacksonville
state: Florida
city: Downers Grove
country: United States
facility: Advocate Medical Group
state: Illinois
city: Naperville
country: United States
facility: Edward Hospital-Advocate Medical Group
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland, Baltimore
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Bayview Medical Center
state: Maryland
city: Farmington Hills
country: United States
facility: Detroit Clinical Research Center
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health
state: Michigan
city: Saint Paul
country: United States
facility: United Heart and Vascular (Allina)
state: Minnesota
city: Kansas City
country: United States
facility: Mid America Heart Institute
state: Missouri
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Lincoln
country: United States
facility: Bryan Heart
state: Nebraska
city: Cherry Hill
country: United States
facility: Cooper Health System
state: New Jersey
city: Charlotte
country: United States
facility: Novant Medical Group, Inc. Presbyterian Sleep Health Charlotte
state: North Carolina
city: Winston-Salem
country: United States
facility: Forsyth Medical Center - Novant
state: North Carolina
city: Cincinnati
country: United States
facility: The Lindner Center for Research and Education at Christ Hospital
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Lancaster
country: United States
facility: Lancaster General Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Hospital of University of Pennsylvania
state: Pennsylvania
city: Memphis
country: United States
facility: Stern Cardiovascular
state: Tennessee
city: San Antonio
country: United States
facility: Methodist Healthcare System
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Marshfield
country: United States
facility: Marshfield Clinic
state: Wisconsin
city: Bad Oeynhausen
country: Germany
facility: Bad Oeynhausen- Heart & Diabetes Center
city: Berlin
country: Germany
facility: Charite Medical School, Campus Virchow-Klinikum
city: Bernau
country: Germany
facility: Bernau-Herzzentruym Brandenburg
city: Bielefeld
country: Germany
facility: Bielefeld-Klinikun
city: Hamburg
country: Germany
facility: Hamburg: Universitares Herzzentrum
city: Kassel
country: Germany
facility: Ambulantes Herzzentrum-Kassel
city: Wroclaw
country: Poland
facility: Fourth Military Hospital
Study officials:
affiliation: Midwest Heart Specialists
name: Maria Rosa Costanzo, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.