Heart Failure, Sleep Apnea, Central, Sleep Disordered Breathing
Conditions
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.
Interventions
DEVICETreatment Group (transvenous stimulation of the phrenic nerve)
device implant, optimal medical therapy and device initiation 1 month post implant.
DEVICEControl Group (Optimal Medical Therapy)
device implant, optimal medical therapy and delayed device initiation (7 months post device implant)
Sponsors
Respicardia, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Participants Experiencing a Reduction in Apnea-hypopnea Index (AHI) | 6 months | 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. |
| Freedom From Related Serious Adverse Events Within 12 Months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Arousal Index (ArI) Change From Baseline at 6 Months | 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. |
| Rapid Eye Movement (REM) Sleep Change From Baseline at 6 Months | 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. |
| Central Apnea Index (CAI) Change From Baseline at 6 Months | 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. |
| Oxygen Desaturation Index 4% (ODI4) Change From Baseline at 6 Months | 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%. |
| Epworth Sleepiness Scale (ESS) Change From Baseline at 6 Months | 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. |
| The Proportion of Participants Experiencing a Marked or Moderate Improvement in Patient Global Assessment at 6 Months | 6 months | The proportion of subjects with a moderate or marked improvement in the Patient Global Assessment from baseline to the 6 month visit |
| Apnea-Hypopnea Index (AHI) Change From Baseline at 6 Months | 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. |
Countries
Germany, Poland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment Group Subjects implanted with the remedē System device who receive optimal medical therapy and remedē System therapy. | 73 |
| Control Group Subjects implanted with the remedē System device who receive optimal medical therapy alone (remedē System inactive through 6 months). | 78 |
| Total | 151 |
Baseline characteristics
| Characteristic | Control Group | Treatment Group | Total |
|---|---|---|---|
| Age, Continuous | 65 years STANDARD_DEVIATION 13 | 65 years STANDARD_DEVIATION 12 | 65 years STANDARD_DEVIATION 13 |
| Apnea-Hypopnea Index (AHI) | 43.7 Events/hour STANDARD_DEVIATION 16.8 | 48.8 Events/hour STANDARD_DEVIATION 19.3 | 46.2 Events/hour STANDARD_DEVIATION 18.2 |
| Arousal Index (ArI) | 43.6 Events/hour STANDARD_DEVIATION 19.1 | 45.5 Events/hour STANDARD_DEVIATION 17.9 | 44.6 Events/hour STANDARD_DEVIATION 18.5 |
| Atrial fibrillation | 32 Participants | 32 Participants | 64 Participants |
| Body mass index (BMI) | 31.3 kg/m2 STANDARD_DEVIATION 6.6 | 30.8 kg/m2 STANDARD_DEVIATION 5.3 | 31.1 kg/m2 STANDARD_DEVIATION 6 |
| Central Apnea Index (CAI) | 26.6 Events/hour STANDARD_DEVIATION 16.1 | 30.0 Events/hour STANDARD_DEVIATION 18 | 28.2 Events/hour STANDARD_DEVIATION 17.1 |
| Concomitant implantable device delivering therapy | 33 Participants | 31 Participants | 64 Participants |
| Coronary artery disease | 44 Participants | 40 Participants | 84 Participants |
| Epworth Sleepiness Scale (ESS) | 9.5 units on a scale STANDARD_DEVIATION 5.8 | 10.2 units on a scale STANDARD_DEVIATION 5.2 | 9.8 units on a scale STANDARD_DEVIATION 5.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 1 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 74 Participants | 72 Participants | 146 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Heart failure | 48 Participants | 48 Participants | 96 Participants |
| Hypertension | 60 Participants | 53 Participants | 113 Participants |
| Left ventricular ejection fraction | 39.4 Percent STANDARD_DEVIATION 12.2 | 39.7 Percent STANDARD_DEVIATION 12.1 | 39.6 Percent STANDARD_DEVIATION 12.1 |
| Obstructive Apnea Index | 2.3 Events/hour STANDARD_DEVIATION 2.7 | 2.6 Events/hour STANDARD_DEVIATION 3.2 | 2.4 Events/hour STANDARD_DEVIATION 3 |
| Oxygen Desaturation Index (ODI4) | 37.5 Events/hour STANDARD_DEVIATION 17.5 | 43.2 Events/hour STANDARD_DEVIATION 21.7 | 40.2 Events/hour STANDARD_DEVIATION 19.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 74 Participants | 70 Participants | 144 Participants |
| Rapid Eye Movement Sleep (REM) | 11.8 Percent STANDARD_DEVIATION 7.1 | 10.4 Percent STANDARD_DEVIATION 7.2 | 11.1 Percent STANDARD_DEVIATION 7.1 |
| Region of Enrollment Germany | 17 participants | 14 participants | 31 participants |
| Region of Enrollment Poland | 11 participants | 10 participants | 21 participants |
| Region of Enrollment United States | 50 participants | 49 participants | 99 participants |
| Sex: Female, Male Female | 6 Participants | 10 Participants | 16 Participants |
| Sex: Female, Male Male | 72 Participants | 63 Participants | 135 Participants |
| Stroke | 6 Participants | 6 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 151 |
| other Total, other adverse events | 53 / 151 |
| serious Total, serious adverse events | 74 / 151 |
Outcome results
Primary
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.
Time frame: 12 months
Population: Intent-to-treat. The study protocol pre-specified that randomized groups be combined to assess freedom from related serious adverse events within 12 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Group | Freedom From Related Serious Adverse Events Within 12 Months | 138 Participants |
Primary
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.
Time frame: 6 months
Population: The population analyzed included all randomized participants who had a 6 month assessment. In addition, Treatment group subjects who did not have a 6 month assessment for reasons related to implant, device or delivered therapy were included as not achieving the endpoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Group | The Proportion of Participants Experiencing a Reduction in Apnea-hypopnea Index (AHI) | 35 Participants |
| Control Group | The Proportion of Participants Experiencing a Reduction in Apnea-hypopnea Index (AHI) | 8 Participants |
p-value: <0.000195% CI: [25, 54]Fisher Exact
Secondary
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.
Time frame: 6 months
Population: Per protocol: excludes patients who did not meet major entry criteria, had therapy programmed to off at the 6-month visit, did not have 6-month PSG results or had unsuccessful implant attempt.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment Group | Apnea-Hypopnea Index (AHI) Change From Baseline at 6 Months | -23.9 Events/hour |
| Control Group | Apnea-Hypopnea Index (AHI) Change From Baseline at 6 Months | 1.1 Events/hour |
p-value: <0.000195% CI: [-31.2, -18.7]t-test, 1 sided
Secondary
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.
Time frame: 6 months
Population: Per protocol: excludes patients who did not meet major entry criteria, had therapy programmed to off at the 6-month visit, did not have 6-month PSG results or had unsuccessful implant attempt.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment Group | Arousal Index (ArI) Change From Baseline at 6 Months | -20.2 Events/hour |
| Control Group | Arousal Index (ArI) Change From Baseline at 6 Months | -5.0 Events/hour |
p-value: <0.000195% CI: [-21.6, -8.7]t-test, 1 sided
Secondary
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.
Time frame: 6 months
Population: Per protocol: excludes patients who did not meet major entry criteria, had therapy programmed to off at the 6-month visit, did not have 6-month polysomnogram (PSG) results or had unsuccessful implant attempt.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment Group | Central Apnea Index (CAI) Change From Baseline at 6 Months | -25.7 Events/hour |
| Control Group | Central Apnea Index (CAI) Change From Baseline at 6 Months | -2.9 Events/hour |
p-value: <0.000195% CI: [-29, -16.6]Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: 6 months
Population: Per protocol: excludes patients who did not meet major entry criteria, had therapy programmed to off at the 6-month visit, did not have 6-month PSG results or had unsuccessful implant attempt.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment Group | Epworth Sleepiness Scale (ESS) Change From Baseline at 6 Months | -3.6 units on a scale |
| Control Group | Epworth Sleepiness Scale (ESS) Change From Baseline at 6 Months | 0.1 units on a scale |
p-value: <0.000195% CI: [-5.5, -2]Wilcoxon (Mann-Whitney)
Secondary
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%.
Time frame: 6 months
Population: Per protocol: excludes patients who did not meet major entry criteria, had therapy programmed to off at the 6-month visit, did not have 6-month PSG results or had unsuccessful implant attempt.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment Group | Oxygen Desaturation Index 4% (ODI4) Change From Baseline at 6 Months | -19.1 Events/hour |
| Control Group | Oxygen Desaturation Index 4% (ODI4) Change From Baseline at 6 Months | 3.6 Events/hour |
p-value: <0.000195% CI: [-28.9, -16.5]t-test, 1 sided
Secondary
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.
Time frame: 6 months
Population: Per protocol: excludes patients who did not meet major entry criteria, had therapy programmed to off at the 6-month visit, did not have 6-month PSG results or had unsuccessful implant attempt.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment Group | Rapid Eye Movement (REM) Sleep Change From Baseline at 6 Months | 1.8 percentage of sleep |
| Control Group | Rapid Eye Movement (REM) Sleep Change From Baseline at 6 Months | -0.6 percentage of sleep |
p-value: 0.024495% CI: [-0.4, 5.1]Wilcoxon (Mann-Whitney)
Secondary
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
Time frame: 6 months
Population: Per protocol: excludes patients who did not meet major entry criteria, had therapy programmed to off at the 6-month visit, did not have 6-month PSG results or had unsuccessful implant attempt. Note: 1 Control subject did not provide a response and is excluded from analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment Group | The Proportion of Participants Experiencing a Marked or Moderate Improvement in Patient Global Assessment at 6 Months | 35 Participants |
| Control Group | The Proportion of Participants Experiencing a Marked or Moderate Improvement in Patient Global Assessment at 6 Months | 4 Participants |
p-value: <0.000195% CI: [40, 68]Fisher Exact