Vascular Endothelial Dysfunction in Sleep Apnea

This double-blind placebo-controlled parallel group randomized study design will be used to test whether 4 weeks of atorvastatin 10 mg daily reduces levels of inflammatory markers in OSA patients treated with CPAP (standard of care). The purpose of this study is to investigate: 1) whether statins reduce endothelial inflammation and pro-thrombotic conditions in OSA, including in patients adherent to CPAP (Aim 1); and 2) whether statins reduce endothelial inflammation and pro-thrombotic conditions by improving endothelial cholesterol metabolism and trafficking in OSA (Aim 2).

Study Overview

• Status: Recruiting
• Conditions: Obstructive Sleep Apnea of Adult
• Intervention / Treatment: Drug: Atorvastatin 10mg; Other: Continuous Positive Airway Pressure Therapy; Drug: Placebo

Detailed Description

Obstructive sleep apnea (OSA), a condition that affects a quarter of American adults, triples the risk for cardiovascular diseases and increases all-cause mortality. Standard therapy with continuous positive airway pressure (CPAP) does not improve cardiovascular risk. Based on the investigators' mechanistic observation that the abnormal cycle of endothelial inflammation can be disrupted with statin therapy, the investigators now propose randomized clinical trial of statins vs. placebo to determine its effects on endothelial dysfunction in OSA patients treated with CPAP, which may provide the basis for practical clinical trials of statins for reducing cardiovascular risk in OSA.

• Study Type: Interventional
• Enrollment (Estimated): 110
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Sanja Jelic, MD; Phone Number: 2125438875; Email: sj366@cumc.columbia.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Irving Medical Center
      • Contact: Sanja Jelic, MD; Phone Number: 212-543-8875; Email: sj366@cumc.columbia.edu
      • Principal Investigator: Sanja Jelic, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aged ≥18 years
• Newly diagnosed with obstructive sleep apnea (OSA) who were never treated with CPAP. OSA is defined as apnea-hypopnea index (AHI) ≥5 events/hour of sleep.

Exclusion Criteria:

• A history of coronary artery disease, heart failure, stroke, diabetes, malignancy, chronic pulmonary, kidney or rheumatologic disease, muscle pain/fatigue, smoking within the past 5 years
• Regular use of any medications

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment; OSA patients who adhered or did not adhere with CPAP who are randomized to receive atorvastatin 10 mg daily.	Drug: Atorvastatin 10mg; Atorvastatin 10 mg daily for 28 days will be randomly allocated to OSA patients regardless of adherence with CPAP. Atorvastatin and placebo will be encapsulated to appear identical and dispensed by the research pharmacy.; Other Names: statin; Other: Continuous Positive Airway Pressure Therapy; CPAP is a standard of care for OSA and will be prescribed by care providers not associated with this study based on clinical indications. The investigators will have no role in prescribing CPAP.; Other Names: CPAP
Placebo Comparator: Control; OSA patients who adhered or did not adhere with CPAP who are randomized to receive placebo daily.	Other: Continuous Positive Airway Pressure Therapy; CPAP is a standard of care for OSA and will be prescribed by care providers not associated with this study based on clinical indications. The investigators will have no role in prescribing CPAP.; Other Names: CPAP; Drug: Placebo; Placebo daily for 28 days will be randomly allocated to OSA patients regardless of adherence with CPAP. Atorvastatin and placebo will be encapsulated to appear identical and dispensed by the research pharmacy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Circulating levels of Angiopoietin-2 after 4 weeks of atorvastatin vs. placebo therapy	Mean circulating levels of Ang-2 will be quantified after 4 weeks of statin or placebo therapy by enzyme-linked immunosorbent assay (ELISA)	4 weeks post-treatment
Interaction of endoplasmic reticulum (ER)-bound vesicle-associated membrane protein-associated protein B (VAPB) with late endosome-bound ORP1L (proximity ligation assay fluorescence area in µm2) after 4 weeks of atorvastatin vs. placebo therapy	Mean Interactions ER-bound VAPB with late endosome-bound ORP1L in harvested endothelial cells (ECs) will be assessed using proximity ligation assay (DuoLink, fluorescence area in µm2) after 4 weeks of atorvastatin or placebo therapy	4 weeks post-treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Circulating levels of von Willebrand factor cleavage products after 4 weeks of atorvastatin vs. placebo	Mean Circulating levels (count) of von Willebrand factor (vWF) cleavage products (low molecular weight (LMW), medium molecular weight (IMW), high molecular weight (HMW)) after 4 weeks of atorvastatin vs. placebo	4 weeks post-treatment
Circulating levels of von Willebrand factor (vWF) cleavage products (low, medium, high molecular weight) at baseline and after 4 weeks of CPAP	Mean Circulating levels (count) of vWF cleavage products (LMW, IMW, HMW) at baseline and after CPAP.	4 weeks post-CPAP
Endothelial cell free cholesterol levels after 4 weeks of atorvastatin vs. placebo	Mean Endothelial cell free cholesterol levels (fluorescence intensity) after 4 weeks of atorvastatin vs. placebo therapy	4 weeks post-treatment
Endothelial cell lipid droplets after 4 weeks of atorvastatin vs. placebo	Mean Endothelial cell lipid droplets (fluorescence area µm2) after 4 weeks of atorvastatin vs. placebo	4 weeks post-treatment
Endothelial cell interactions between CD59 and Weibel Palade Bodies (WPBs) after 4 weeks of atorvastatin vs. placebo	Mean Endothelial cell interactions between CD59 and Weibel Palade Bodies (fluorescence area µm2) after 4 weeks of atorvastatin vs. placebo	4 weeks post-treatment
Circulating levels of Angiopoietin-2 at baseline and after 4 weeks of CPAP therapy	Mean Circulating levels of Angiopoietin-2 after 4 weeks of CPAP therapy quantified by ELISA	4 weeks post-CPAP
Interaction of ER-bound VAPB with late endosome-bound ORP1L (proximity ligation assay fluorescence area in µm2) at baseline and after 4 weeks of CPAP therapy	Mean Interaction of ER-bound VAPB with late endosome-bound ORP1L (proximity ligation assay fluorescence area in µm2) after 4 weeks of CPAP therapy	4 weeks post-CPAP
Endothelial cell nuclear factor kappa B (NF-κB) nuclear fluorescence intensity after 4 weeks of atorvastatin vs. placebo	Mean Endothelial cell NF-kB nuclear fluorescence intensity after 4 weeks of atorvastatin vs. placebo	4 weeks post-treatment
Circulating levels of E-selectin after 4 weeks of atorvastatin vs. placebo therapy	Mean Circulating levels of E-selectin after 4 weeks of atorvastatin vs. placebo therapy quantified by ELISA	4 weeks post-treatment
Endothelial cell messenger ribonucleic acid (mRNA) expression of EC adhesion molecules after 4 weeks of atorvastatin vs. placebo	Mean Endothelial cell mRNA expression of EC adhesion molecules after 4 weeks of atorvastatin vs. placebo quantified by reverse transcription polymerase chain reaction (RT-PCR)	4 weeks post-treatment

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Sanja Jelic, MD, Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): October 3, 2022
• Primary Completion (Estimated): February 28, 2026
• Study Completion (Estimated): February 28, 2026

Study Registration Dates

• First Submitted: March 10, 2022
• First Submitted That Met QC Criteria: March 11, 2022
• First Posted (Actual): March 21, 2022

Study Record Updates

• Last Update Posted (Estimated): February 6, 2024
• Last Update Submitted That Met QC Criteria: February 5, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: CPAP; Atorvastatin
• 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; Sleep Apnea, Obstructive; Apnea; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin
• Other Study ID Numbers: AAAT8810; 2R01HL106041 (U.S. NIH Grant/Contract)

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