Obstructive Sleep Apnea of Adult
Conditions
Keywords
CPAP, Atorvastatin
Brief summary
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).
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.
Interventions
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.
DRUGPlacebo
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.
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.
Sponsors
Columbia University
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Active drug and placebo will be made identical in appearance and given to participants in a blinded fashion.
Intervention model description
Randomized double blind design
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 4 weeks post-treatment | 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 |
| Circulating levels of Angiopoietin-2 after 4 weeks of atorvastatin vs. placebo therapy | 4 weeks post-treatment | Mean circulating levels of Ang-2 will be quantified after 4 weeks of statin or placebo therapy by enzyme-linked immunosorbent assay (ELISA) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Circulating levels of von Willebrand factor (vWF) cleavage products (low, medium, high molecular weight) at baseline and after 4 weeks of CPAP | 4 weeks post-CPAP | Mean Circulating levels (count) of vWF cleavage products (LMW, IMW, HMW) at baseline and after CPAP. |
| Endothelial cell free cholesterol levels after 4 weeks of atorvastatin vs. placebo | 4 weeks post-treatment | Mean Endothelial cell free cholesterol levels (fluorescence intensity) after 4 weeks of atorvastatin vs. placebo therapy |
| Endothelial cell lipid droplets after 4 weeks of atorvastatin vs. placebo | 4 weeks post-treatment | Mean Endothelial cell lipid droplets (fluorescence area µm2) after 4 weeks of atorvastatin vs. placebo |
| Circulating levels of Angiopoietin-2 at baseline and after 4 weeks of CPAP therapy | 4 weeks post-CPAP | Mean Circulating levels of Angiopoietin-2 after 4 weeks of CPAP therapy quantified by ELISA |
| 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 | 4 weeks post-CPAP | Mean Interaction of ER-bound VAPB with late endosome-bound ORP1L (proximity ligation assay fluorescence area in µm2) after 4 weeks of CPAP therapy |
| Endothelial cell nuclear factor kappa B (NF-κB) nuclear fluorescence intensity after 4 weeks of atorvastatin vs. placebo | 4 weeks post-treatment | Mean Endothelial cell NF-kB nuclear fluorescence intensity after 4 weeks of atorvastatin vs. placebo |
| Circulating levels of E-selectin after 4 weeks of atorvastatin vs. placebo therapy | 4 weeks post-treatment | Mean Circulating levels of E-selectin after 4 weeks of atorvastatin vs. placebo therapy quantified by ELISA |
| Endothelial cell interactions between CD59 and Weibel Palade Bodies (WPBs) after 4 weeks of atorvastatin vs. placebo | 4 weeks post-treatment | Mean Endothelial cell interactions between CD59 and Weibel Palade Bodies (fluorescence area µm2) after 4 weeks of atorvastatin vs. placebo |
| Endothelial cell messenger ribonucleic acid (mRNA) expression of EC adhesion molecules after 4 weeks of atorvastatin vs. placebo | 4 weeks post-treatment | 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) |
| Circulating levels of von Willebrand factor cleavage products after 4 weeks of atorvastatin vs. placebo | 4 weeks post-treatment | 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 |
Countries
United States
Contacts
CONTACTSanja Jelic, MD
PRINCIPAL_INVESTIGATORSanja Jelic, MD
Columbia University
Outcome results
None listed