Sleep Apnea in Elderly

Pathophysiology-Guided Therapy for Sleep Apnea in the Elderly

Sleep-disordered breathing (SDB or sleep apnea) is very common among elderly Veterans and leads to increased morbidity and mortality in this population. The proposal aims to identity whether oxygen, finasteride and acetazolamide can be effective in reducing unstable breathing and eliminating sleep apnea in the elderly via different mechanisms. This proposal will enhance the investigators' understanding of the pathways that contribute to the development of sleep apnea in the elderly. The investigators expect that the results obtained from this study will positively impact the health of Veterans by identifying new treatment modalities for sleep apnea. A cumulative effect of the investigators' research will fulfill the long-term goal of improving the quality of life of elderly Veterans suffering from sleep apnea and its potential life-threatening complications.

Study Overview

• Status: Recruiting
• Conditions: Sleep Apnea; Elderly Adults
• Intervention / Treatment: Other: Hyperoxia/oxygen; Drug: Acetazolamide; Drug: Finasteride

Detailed Description

Sleep apnea-hypopnea syndrome (SAHS) has a high prevalence and is associated with adverse cardiovascular consequences in elderly Veterans. Positive airway pressure therapy is deemed cumbersome and often associated with non-adherence to therapy. This proposal will investigate whether alternative therapies can be developed by modulating specific physiologic mechanisms of ventilatory control. Specifically, the investigators will study whether interventions with sustained hyperoxia (Aim 1), finasteride (Aim 2) and acetazolamide (Aim 3) will reduce breathing instability during sleep by reducing chemoresponsiveness and/or increasing cerebrovascular reactivity (CVR) in order to alleviate sleep disordered breathing in the elderly with sleep apnea. The proposed aims will also allow us to delineate key mechanisms of breathing instability in the elderly. The investigators envision that the results obtained from this project will ultimately allow us to develop novel alternative therapies for sleep apnea in the elderly. We will also compare CVR in young vs older adults

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Ruchi Rastogi, MSc; Phone Number: (313) 576-1000; Email: ruchi.rastogi@va.gov

Study Locations

• United States
  • Michigan
    • Detroit, Michigan, United States, 48201-1916
      • Recruiting
      • John D. Dingell VA Medical Center, Detroit, MI
      • Principal Investigator: Susmita Chowdhuri, MD
      • Contact: Edi Levi, MD; Phone Number: 313-576-4451; Email: edi.levi@va.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 89 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Adults who are 60 years old and older, with mild to moderate sleep apnea with AHI >/=5 to 20/hr with central, obstructive, mixed apneas and hypopneas.
• For the finasteride protocol elderly men with above criteria will be enrolled.

Exclusion Criteria:

• Patients with severe sleep apnea (AHI>20/hr)
• Patients with history of prostate cancer
• Males with hypogonadism
• History of cardiac disease, including myocardial infarction
• Bypass surgery
• Atrial and ventricular tachy-bradycardias
• Systolic congestive heart failure and Cheyne-Stokes respiration
• Current unstable angina
• Stroke
• Schizophrenia
• Untreated hypothyroidism
• Seizure disorder
• Preexisting renal failure and liver disorders
• Failure to give informed consent.
• Patients with significant pulmonary diseases by history and abnormal pulmonary function testing, including moderate obstructive/restrictive lung/chest wall disorders with resting oxygen saturation of <96% or on supplemental oxygen

• Patients on certain medications including:

  • study drugs
  • sympathomimetics/parasympathomimetics or their respective blockers
  • narcotics
  • antidepressants
  • anti-psychotic agents
  • other central nervous system (CNS) altering medications
  • current alcohol, tobacco or recreational drug use
• Patients with BMI>34kg/m2 will be excluded to avoid the effects of morbid obesity on pulmonary mechanics and ventilatory control
• Elderly with unstable gait or mobility issues that may preclude safe participation
• Individuals with allergy to finasteride or acetazolamide will be excluded from the specific protocol
• Pregnant women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Hyperoxia; Determine the effect of sustained hyperoxia overnight vs room air overnight on ventilatory control during sleep, including the apneic threshold, carbon-dioxide reserve and chemosensitivity measured via pressure support ventilation (PSV) during (non-rapid eye movement sleep) NREM sleep.	Other: Hyperoxia/oxygen; The ventilatory effects of brief hyperoxia will be assessed by analyzing control breaths on room air immediately preceding the hyperoxic exposure, and comparing with the primary end-point, nadir minute ventilation breath, immediately following the brief hyperoxic exposure
Experimental: Acetazolamide (ACZ); Determine the effect of acetazolamide on cerebrovascular responsiveness to CO2 during wake and sleep. Participants will receive oral ACZ therapy for 7 days prior to the experimental night, on the night of the study and the subsequent night when polysomnography (PSG) will be performed.	Drug: Acetazolamide; Participants with sleep apnea will ingest capsules containing either placebo or acetazolamide 500 mg twice a day for 5 days. On the final 2 consecutive nights while still on ACZ, the investigators will perform i) physiology tests and ii) in-lab follow-up PSG.
Experimental: Finasteride; Determine the effect of oral finasteride therapy vs placebo for 1 month on SDB and the AT and chemosensitivity during NREM sleep.	Drug: Finasteride; Elderly males with sleep apnea and adequate testosterone levels will ingest placebo vs finasteride, at 5 mg a day for 1 month (mo). After 1 mo, while still on the drug, on the final 2 consecutive nights, the investigators will perform i) physiology tests and ii) in-lab follow-up PSG. Blood tests will be performed to check sex hormone levels. A washout period of 1 month prior to cross-over to the alternate arm (placebo).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Apneic threshold- a measure of breathing instability	Measures of breathing instability including: Apneic threshold: this is the end-tidal Co2 at which a central apnea closes to a hypopnea is produced.	2 days to 30 days
Cerebrovascular responsiveness to carbon-dioxide	Cerebrovascular response to different levels of CO2: this is a measure of the response of the cerebral blood flow to changes in carbon dioxide levels and is used as a measure of ventilatory control of breathing	7 days
Ventilatory responsiveness	Hypocapnic ventilatory response; this is calculated as the change in minute ventilation for corresponding changes in PETCO2.	2 days to 30 days
Carbon -dioxide reserve	This is a derived measure. This is calculated as the difference between the apneic threshold PETCO2 (given above) and the control PETCO2.	2 days to 30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Apnea hypopnea index	Apnea hypopnea index- is a measure of severity of sleep apnea - this is calculated as the total number of apneas and hypopneas recorded during a sleep study divided by the total sleep time during the sleep study.	2 days to 30 days

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Susmita Chowdhuri, MD, John D. Dingell VA Medical Center, Detroit, MI

Publications and helpful links

General Publications

• Rastogi R, Badr MS, Ahmed A, Chowdhuri S. Amelioration of sleep-disordered breathing with supplemental oxygen in older adults. J Appl Physiol (1985). 2020 Dec 1;129(6):1441-1450. doi: 10.1152/japplphysiol.00253.2020. Epub 2020 Sep 24.

Study record dates

Study Major Dates

• Study Start (Actual): July 3, 2015
• Primary Completion (Estimated): June 30, 2024
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: January 29, 2016
• First Submitted That Met QC Criteria: March 3, 2016
• First Posted (Estimated): March 9, 2016

Study Record Updates

• Last Update Posted (Actual): August 18, 2023
• Last Update Submitted That Met QC Criteria: August 16, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: sleep apnea; acetazolamide; hyperoxia; finasteride; chemoresponsiveness; cerebrovascular response; apneic threshold; carbon-dioxide reserve
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Signs and Symptoms, Respiratory; Sleep Apnea Syndromes; Apnea; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Urological Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Carbonic Anhydrase Inhibitors; Natriuretic Agents; Diuretics; Anticonvulsants; Hormone Antagonists; Steroid Synthesis Inhibitors; 5-alpha Reductase Inhibitors; Acetazolamide; Finasteride
• Other Study ID Numbers: PULM-008-14F

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No