Central Apnea in Heart Failure: Physiological Mechanisms to Inform Treatment

NCT07210606 | Not Yet Recruiting Phase 4 FDA Drug

• 2 other identifiers: NURR-010-25S2I01RD001576-07A1
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 1

Brief Summary

Central sleep apnea (CSA) is common in patients with heart failure and those using opioid analgesics. Unfortunately, effective treatment of central apnea remains elusive, pressure therapy given the modest efficiency of positive airway pressure therapy. The focus of this proposal is to identify mechanistic pathways to guide future therapeutic interventions for central sleep apnea based on the strong premise that multi-modality therapy will normalize respiration and hence mitigate adverse long-term consequences of CSA. The investigators' proposed studies will test combination therapies, including positive airway pressure (PAP) plus a pharmacological agent who have heart failure or are using opioid analgesics. The investigators anticipate that findings will inform future clinical trials to improve care and quality of life among Veterans suffering from central sleep apnea, which remains difficult to treat using existing approaches.

Conditions

Sleep Disordered Breathing; Able Bodied

Keywords

Central Sleep Apnea; Polysomnography (PSG); Respiratory Arousal Threshold; Apnea Hypopnea Index; Central Apnea Hypopnea Index; Breathing Instability; Apneic Threshold (AT); Peripheral Chemoreflex Sensitivity; CO2 reserve; Plant gain; Controller gain; Cheyne Stokes Breathing (CSB); Carotid Body Function; Peripheral Chemoresponsiveness; Heart Failure

Outcome Measures

Primary Outcomes (1)

• CO2 Reserve

  CO2 reserve is the requisite change to induce central apnea to as the CO2 reserve, which can be positive or negative.

  120 days

Secondary Outcomes (5)

• Peripheral Chemoresponsiveness

  120 days

• Arousal Threshold

  120 days

• Carotid body function

  120 days

• Controller gain

  120 days

• Plant gain

  120 days

Study Arms (2)

Trazodone

ACTIVE COMPARATOR

To determine the effect of dampening respiratory arousals. The investigators hypothesize that PAP therapy with trazodone at 100 mg will be superior to CPAP alone in widening the CO2 reserve during sleep, decreasing respiratory arousals, and increasing the arousal threshold.

Drug: Trazodone + PAP therapy

Oxygen

ACTIVE COMPARATOR

To determine the effect of dampening peripheral chemoreceptor sensitivity. The investigators hypothesize that supplemental oxygen will be superior to CPAP alone in widening the CO2 reserve during sleep. The secondary analysis will use CAI as supplemental oxygen, which may obscure the detection of hypopneas based on desaturation.

Drug: Oxygen + PAP therapy

Interventions

Trazodone + PAP therapy DRUG

The central apnea index and the apneic threshold will be compared under two conditions: trazodone or placebo. In addition, participants will get PAP therapy during both the conditions.

Trazodone

Oxygen + PAP therapy DRUG

The central apnea index and the apneic threshold will be compared under two conditions: oxygen or room air. In addition, participants will get PAP therapy during both the conditions.

Oxygen

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and Women Veterans with central sleep apnea, defined as Apnea Hypopnea Index (AHI)\>15/hour with CAHI\>5/hour, will be included with the experiments.
• Those with chronic, stable heart failure with reduced ejection fraction, receiving stable optimized guideline-based therapy and no hospitalizations or change in the medical regimen for the past 90 days before enrollment.

You may not qualify if:

• less than 18 years old
• pregnant or breastfeeding females
• moderate or severe obstructive or restrictive lung disease, including supplemental o2 use
• current treatment for CSA, including any form of PAP in the past three months, or phrenic nerve situation.
• too ill to engage in the study procedures, inability to provide consent for participation.
• a history of cardiac arrhythmia
• Alcohol or substance abuse (less than 90 days sobriety) or current participation in a treatment program
• depression or a history of suicidality
• severe insomnia (ISI\>21) or reported short sleep duration (\<6 hours)
• PAP-emergent central sleep apnea
• Lack of PAP acceptance/adherence after a one-week home PAP trial after enrollment.
• Prolonged QT on baseline ECG, using medications that inhibit CYP3A4
• Patients with severe renal impairment (GFR \< 20ml/min/1.73m2) or end-stage renal disease

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (1)

John D. Dingell VA Medical Center, Detroit, MI

Detroit, Michigan, 48201-1916, United States

Location

MeSH Terms

Conditions

Sleep Apnea Syndromes; Sleep Apnea, Central; Cheyne-Stokes Respiration; Heart Failure

Interventions

Trazodone; Oxygen

Condition Hierarchy (Ancestors)

Apnea; Respiration Disorders; Respiratory Tract Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyridones; Pyridines; Chalcogens; Elements; Inorganic Chemicals; Gases

Study Officials

• M Safwan Badr, MD

  John D. Dingell VA Medical Center, Detroit, MI

  PRINCIPAL INVESTIGATOR

Central Study Contacts

M S Badr, MD

CONTACT

(313) 576-1000; sbadr@med.wayne.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: Specific Aim (1) is to determine the effect of decreasing respiratory arousals on the propensity to CSA. The investigators hypothesize that combined therapy with PAP and trazodone will be superior to PAP alone in elevating the arousal threshold, widening the CO2 reserve, and decreasing CSA indices. Specific Aim (2) is to determine the effect of decreased peripheral chemoreceptor sensitivity on the propensity to CSA. The investigators hypothesize that combined therapy with PAP and supplemental O2 will be superior to PAP alone in widening the CO2 reserve, reducing controller gain, and decreasing CSA indices.

Study Record Dates

• First Submitted: September 29, 2025
• First Posted: October 7, 2025
• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): June 30, 2030
• Study Completion (Estimated): December 31, 2030
• Last Updated: January 7, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)