Endothelial Function in Obstructive Sleep Apnea

NCT03122639 | Completed Early Phase 1 DMC FDA Drug

• 2 other identifiers: AAAR04442R01HL106041-06A1
• Study Type: interventional
• Target: 106
• Locations: 1 country
• Sites: 1

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.

Conditions

Obstructive Sleep Apnea of Adult

Outcome Measures

Primary Outcomes (1)

• Change in proportion of CD59 on the endothelial cell (EC) surface (the percent [%] of the total cellular CD59 protein that is expressed on the endothelial cell surface).

  Outcome 1 will be assessed before and after 4 weeks of atorvastatin or placebo. Each patient 28-day follow-up value will be compared with baseline value. There is no reference range for this marker of complement regulation. The percent of total CD59 located on the EC plasma membrane will be quantified using immunofluorescence and confocal microscopy. This is a single outcome measure. The unit is percent (%) of the total cellular CD59 protein that is expressed on the endothelial cell surface.

  Up to 28 days

Secondary Outcomes (2)

• MAC deposition on EC surface (measurement unit is fluorescent area quantified as micrometer square).

  Up to 28 days

• ORP1L (late endosome protein) and VAPB (endoplasmic reticulum protein) interaction (measurement unit is fluorescent area quantified as micrometer square).

  1 day

Other Outcomes (5)

• Derlin and VAPB interaction

  1 day

• Lipid droplets in endothelial cells

  1 day

• free cholesterol content in endothelial cells

  1 day

Study Arms (2)

Treatment

ACTIVE COMPARATOR

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).

Drug: Atorvastatin 10mg

Control

PLACEBO COMPARATOR

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).

Drug: Placebo

Interventions

Atorvastatin 10mg 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.

Also known as: statin

Treatment

Placebo 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.

Control

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Columbia University: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

Columbia University Medical Center

New York, New York, 10032, United States

Location

Related Publications (1)

• 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.

  PMID: 36912897 DERIVED

MeSH Terms

Interventions

Atorvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Enzyme Inhibitors; Lipid Regulating Agents; Therapeutic Uses

Study Officials

• Sanja Jelic, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Active drug and placebo will be made identical in appearance and given to participants in a blinded fashion.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: Randomized double blind design

Study Record Dates

• First Submitted: April 12, 2017
• First Posted: April 21, 2017
• Study Start: September 1, 2017
• Primary Completion: January 30, 2020
• Study Completion: May 7, 2021
• Last Updated: September 19, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)