Endothelial Function in Obstructive Sleep Apnea

NCT ID: NCT03122639

Last Updated: 2024-09-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 106 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-09-01
• Study Completion Date: 2021-05-07

Brief Summary

Obstructive sleep apnea (OSA), a condition that affects a quarter of the Western adults, triples the risk for cardiovascular diseases and increases all-cause mortality. Intermittent hypoxia (IH) during transient cessation of breathing in OSA leads to endothelial inflammation, a key step in the initiation and progression of cardiovascular disease. However, the mechanisms that mediate IH-induced endothelial inflammation remain unclear and, consequently, no targeted therapy is available for vascular manifestations of OSA. Using endothelial cells (ECs) freshly harvested from OSA patients, they study team has identified impaired complement inhibition as an initial stimulus for endothelial inflammation in IH, thereby linking for the first time complement activation to vascular risk in OSA. The investigators found that a major complement inhibitor cluster of differentiation (CD59), a plasma membrane protein that inhibits the formation of the terminal complement membrane attack complex (MAC) and protects host cells from complement injury, is internalized from the EC surface in OSA patients. Consequent MAC deposition initiates endothelial inflammation in IH. Importantly, the investigators showed that IH does not significantly affect inflammation in ECs in the absence of complement, suggesting that complement activation has an essential role in endothelial inflammation in OSA. Interestingly, internalization of CD59 in IH appears to be cholesterol-dependent and statins prevent MAC deposition on ECs in IH in a CD59-dependent manner, suggesting a novel therapeutic strategy to reduce vascular risk in OSA. This led the study team to hypothesize that IH-induced cellular cholesterol accumulation reduces complement inhibition via increased internalization of CD59 from the EC surface leading to increased MAC deposition, and that treatment of OSA with continuous positive airway pressure (CPAP) and/or statins reverses endothelial dysfunction by restoring complement inhibition.

Detailed Description

To address the hypothesis, the investigators seek to determine whether statins prevent endothelial dysfunction in OSA by restoring complement inhibition. The preliminary data indicate that the expression of CD59 on the EC surface is preserved in OSA patients who are receiving statins and that statins prevent CD59 internalization and MAC deposition in IH leading to reduced inflammation. The study proposes to determine whether statins restore endothelial protection against complement activity in OSA patients using double-blind placebo-controlled parallel group randomized study design. The hypothesis: The proportion of CD59 on the EC surface is increased while MAC deposition is decreased after 4 weeks of atorvastatin 10 mg daily compared with placebo in OSA patients who adhere with CPAP or do not adhere with CPAP.

The proposed studies may advance our understanding of vascular dysfunction in OSA and provide the basis for large, long-term clinical trials of novel therapeutic strategies, such as addition of statins to the standard CPAP therapy, for preventing and/or reversing vascular risk in OSA.

Conditions

Obstructive Sleep Apnea of Adult

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: QUADRUPLE

Study Groups

Treatment

OSA patients who adhered or did not adhere with CPAP will be randomized 1:1 to treatment (atorvastatin 10 mg daily) or control group (placebo).

Group Type: ACTIVE_COMPARATOR

Atorvastatin 10mg

Intervention Type: DRUG

Atorvastatin 10 mg daily for 28 days will be randomly allocated to OSA patients regardless of adherence with CPAP. 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. Atorvastatin and placebo will be encapsulated to appear identical and dispensed by the research pharmacy.

Control

OSA patients who adhered or did not adhere with CPAP will be randomized 1:1 to treatment (atorvastatin 10 mg daily) or control group (placebo).

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo daily for 28 days will be randomly allocated to OSA patients regardless of adherence with CPAP. 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. Atorvastatin and placebo will be encapsulated to appear identical and dispensed by the research pharmacy.

Interventions

Atorvastatin 10mg

Atorvastatin 10 mg daily for 28 days will be randomly allocated to OSA patients regardless of adherence with CPAP. 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. Atorvastatin and placebo will be encapsulated to appear identical and dispensed by the research pharmacy.

Intervention Type: DRUG

Placebo

Placebo daily for 28 days will be randomly allocated to OSA patients regardless of adherence with CPAP. 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. Atorvastatin and placebo will be encapsulated to appear identical and dispensed by the research pharmacy.

Intervention Type: DRUG

Other Intervention Names

statin

Eligibility Criteria

Inclusion Criteria

• Patients aged ≥18 years with newly diagnosed 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Columbia University

OTHER

Sponsor Role: lead

Responsible Party

Sanja Jelic

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Sanja Jelic, MD

Role: PRINCIPAL_INVESTIGATOR

Columbia University

Locations

Columbia University Medical Center

New York, New York, United States

Countries

United States

References

Shah R, Patel N, Emin M, Celik Y, Jimenez A, Gao S, Garfinkel J, Wei Y, Jelic S. Statins Restore Endothelial Protection against Complement Activity in Obstructive Sleep Apnea: A Randomized Clinical Trial. Ann Am Thorac Soc. 2023 Jul;20(7):1029-1037. doi: 10.1513/AnnalsATS.202209-761OC.

Reference Type: DERIVED

PMID: 36912897 (View on PubMed)

Other Identifiers

2R01HL106041-06A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

AAAR0444

Identifier Type: -

Identifier Source: org_study_id