Treatment of Sleep Apnea in Patients With Cervical Spinal Cord Injury

• Sponsor: John D. Dingell VA Medical Center
• Collaborator: United States Department of Defense
• Information provided by (Responsible Party): John D. Dingell VA Medical Center

Study Description

Brief Summary:

This study will investigate potential therapeutic approaches for sleep-disordered breathing (SDB) in patients with chronic cervical spine injury (>6 months post-injury).

Condition or disease	Intervention/treatment	Phase
Sleep Apnea; Spinal Cord Injury	Procedure: Acute episodic hypoxia; Procedure: Supplemental oxygen; Drug: Trazodone; Drug: Placebo; Procedure: Sham	Phase 4

Detailed Description:

Patients with cervical spinal cord injury demonstrate central sleep disordered breathing manifesting as central sleep apnea or a periodic breathing pattern. Understanding the causes of central sleep apnea may be critically important to understanding upper airway obstruction in susceptible individuals, given the critical role of ventilatory motor output in maintaining upper airway patency as evidenced by upper airway narrowing or occlusion at the nadir of ventilator drive during periodic breathing. This study is likely to identify therapeutic strategies that could be tested in large clinical trials, with the ultimate goal of improving quality of life among patients with cervical SCI who also experience central sleep disordered breathing.

To this end the research proposal is aimed as follows:

Specific Aim 1: Test the hypothesis that patients with cervical SCI will demonstrate greater magnitude of long-term facilitation (LTF) following episodic hypoxia during sleep, compared to patients with thoracic Spinal cord injury. This aim will be accomplished by measuring the effect of acute episodic hypoxic ventilation and upper airway mechanics in both groups.

Specific Aim 2: Test the hypothesis that dampening peripheral chemoreceptor activity in patients with cervical SCI and central sleep disordered breathing (SDB) with supplemental oxygen will reduce central respiratory events and decrease respiratory variability during sleep. The aim will be accomplished by providing supplemental oxygen to participants with cervical SCI and central SDB.

Specific Aim 3: Test the hypothesis that administration of trazodone, in patients with cervical spinal cord injury and central SDB will decrease respiratory related arousals and central apnea index, and the propensity to develop central apnea, compared to placebo. To accomplish this aim, the investigators will test the acute effect of trazodone on respiratory related arousals and central sleep apnea, and the chronic effect on central apnea indices and the CO2 reserve.

The investigators will study subjects with SCI at T6 or above who are not on artificial ventilation. To characterize the sleep and breathing state of each subject, polysomnography and upper airway collapsibility will be measured at baseline. Then the following experiments will be conducted: an episodic hypoxia protocol vs normoxia will be used to determine whether cervical SCI will demonstrate greater magnitude of LTF. Experiments will be conducted to see whether dampening peripheral chemoreceptor activity in cervical SCI by giving supplemental oxygen will reduce the central respiratory events and reduce the breathing variability during sleep. A cross over experiment will be done to see whether administration of trazodone in patients with cervical SCI and central SDB decreases respiratory-related arousals and central apnea. The participant will be given the drug/placebo for one week then cross over after a 1 week wash out period to placebo.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Participant)
• Primary Purpose: Other
• Official Title: Treatment of Sleep Apnea in Patients With Cervical Spinal Cord Injury
• Actual Study Start Date: June 9, 2017
• Estimated Primary Completion Date: September 2020
• Estimated Study Completion Date: February 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Acute episodic hypoxia; To test development of ventilatory augmentation following episodic hypoxia, defined as increased Hypoxic Ventilatory Response (HVR) from early to late hypoxic exposure episodes.	Procedure: Acute episodic hypoxia; The subjects will undergo 30 minutes of baseline monitoring followed by 15 episodes of one minute of episodic hypoxia with supplemental CO2 to maintain isocapnia. This is followed by a 45 minute recovery period.; Procedure: Sham; Room air will be administered instead of episodic hypoxia or supplemental oxygen..
Experimental: Supplemental oxygen; To use supplemental oxygen to decrease peripheral chemoreceptor activity in patients with SCI and central SDB. In addition, perform a repeat evaluation after treatment with supplemental oxygen or sham O2 for 6 weeks to determine if correction of chronic intermittent hypoxia, which mitigates sensory LTF, results in decreased propensity to central apnea.	Procedure: Supplemental oxygen; Supplemental oxygen therapy for 6 weeks; Procedure: Sham; Room air will be administered instead of episodic hypoxia or supplemental oxygen..
Experimental: Trazodone or placebo; examine the effect of trazodone on breathing during sleep	Drug: Trazodone; 100mg before bedtime; Drug: Placebo; One placebo pill before-bedtime

Outcome Measures

Primary Outcome Measures :

1. Change in Tidal Volume [ Time Frame: 1 Week ]
   Change in tidal volume from baseline to recovery period.
2. Change in CO2 reserve (Delta-PETCO2-AT) [ Time Frame: 1 Week ]
   CO2 reserve (Delta-PETCO2-AT) will be measured after the one week treatment with trazodone and placebo and will be compared to baseline.
3. Change in Apnea Hypopnea Index (AHI) [ Time Frame: 1 week ]
   AHI will be measured after the one week treatment with trazodone and placebo and compared to baseline.
4. Change in hypocapnic apneic threshold [ Time Frame: 1 week ]
   Hypocapnic apneic threshold with will be measured after the one week treatment with trazodone and placebo and compared to baseline.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 89 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

1. healthy adults between the ages of 18 - 89
2. chronic spinal cord injury patients (T6 and above), > 3 months since injury and not on mechanical ventilation, and have not received mechanical ventilation via tracheostomy in the past.

Exclusion Criteria:

1. subjects ≤ 17 yrs old
2. Pregnant and lactating females
3. History of head trauma that resulted in neurological symptoms or loss of consciousness
4. advanced heart, lung, metabolic, liver or chronic kidney disease.
5. severe obstructive or restrictive respiratory defect by PFTs or history of tracheostomy
6. extreme obesity defined for this protocol as BMI ≥ 40 kg/m2 (to avoid the effect of morbid obesity on ventilation.

Contacts and Locations

Contacts

Contact: M Safwan Badr, M.D.; 313-576-3548; m.badr@va.gov

Locations

United States, Michigan

John D. Dingell VA Medical Center; Recruiting

Detroit, Michigan, United States, 48201

Contact: M. Safwan Badr, MD 313-576-3548

Sponsors and Collaborators

John D. Dingell VA Medical Center

United States Department of Defense

Investigators

• Principal Investigator: M Safwan Badr, M.D.; John D. Dingell VA Medical Center

More Information

• Responsible Party: John D. Dingell VA Medical Center
• ClinicalTrials.gov Identifier: NCT02922894 History of Changes
• Other Study ID Numbers: 1607015110
• First Posted: October 4, 2016
• Last Update Posted: May 30, 2019
• Last Verified: May 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Wounds and Injuries; Apnea; Sleep Apnea Syndromes; Spinal Cord Injuries; Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Spinal Cord Diseases; Central Nervous System Diseases; Trauma, Nervous System; Trazodone; Anti-Anxiety Agents; Tranquilizing Agents; Central Nervous System Depressants; Physiological Effects of Drugs; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Serotonin Agents; Antidepressive Agents, Second-Generation; Antidepressive Agents