Extracellular microRNA: Biomarkers of Endothelial Dysfunction in Obese Adolescents & Adults With Obstructive Sleep Apnea

Extracellular Micro RNA (miR) (Extracellular Vesicle (EV)-Associated & Non-EV-associated miRs) Identify and Mediate Endothelial Dysfunction in Obesity and Obstructive Sleep Apnea in Adolescents & Young Adults

Using a prospective observational approach and a clinical trial design comparing the effectiveness of continuous positive airway pressure to diet and exercise, investigators plan to evaluate how obstructive sleep apnea (OSA) leads to endothelial dysfunction in adolescents and young adults and whether treatment of OSA can improve endothelial dysfunction. Concurrently, investigators will measure miR 92a/miR 210 levels in all subjects at baseline and following therapy to determine whether miR 92a/miR 210 levels reliably predict endothelial dysfunction in patients and responses to therapy.

Study Overview

• Status: Not yet recruiting
• Conditions: Obstructive Sleep Apnea
• Intervention / Treatment: Device: Continuous Positive Airway Pressure; Other: Diet And Exercise

Detailed Description

Investigators will randomize 100 OSA patients (age 13-21) to receive either continuous positive airway pressure (CPAP) plus baseline diet/exercise (n=50) or medical management (intensive diet and exercise; n=50). Only children in whom adenotonsillectomy is contraindicated (morbid obesity, history of adenotonsillectomy, lack of adenotonsillar hypertrophy) will be included. Investigators will conduct a randomized prospective comparative effectiveness study to assess the impact of treatment on OSA on endothelial function (peripheral arterial tonometry-EndoPAT). In addition to diagnostic polysomnography and EndoPAT at baseline, EV (extracellular vesicle) and non EV derived miR 92a/miR 210 concentrations, inflammatory cytokines concentrations, and body anthropometry will be measured. Following 3 mos of therapy and after 6mos of therapy, investigators will re-evaluate EndoPAT, EV and non EV derived miR 92a/miR 210 concentrations, inflammatory cytokines, and body anthropometry.

Throughout the study, investigators will maintain weekly telephone contact and monthly face-to-face visits as per standard of care in both groups to ensure ongoing success. In the medical management group (intensive diet and exercise), diet and exercise will be tracked by maintaining weekly telephone contact and monthly face-to-face visits with a registered dietician. For the CPAP group, investigators will also maintain weekly telephone contact and monthly face-to-face visits with a sleep technician to review mask fitting, and adherence reports, to optimize adherence to CPAP therapy.

Following completion at six months, polysomnography will be repeated.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Rakesh Bhattacharjee, MD; Phone Number: 858-966-5846; Email: rakesh@ucsd.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 21 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Otherwise healthy children and young adults with a diagnosis of obstructive sleep apnea based on polysomnography criteria of an obstructive apnea hypopnea index > 10 events/hr.
• For children a BMI range up to 99.7% and for adults BMI up to 32 kg/m2 is used.

Exclusion Criteria:

• The presence of elevated blood pressure
• The presence of diabetes or pre-diabetes
• The presence of craniofacial anomalies
• The presence of neuromuscular disorders
• The presence of syndromic or defined genetic abnormalities
• Pregnancy
• History of smoking (any smoking within the prior 6 mos or >5 pack years total)
• The presence of infectious disease (e.g. including hepatitis B, C, HIV etc.)
• The presence of collagen vascular disease (e.g. lupus, arthritis, scleroderma, polymyositis, mixed-connective tissue disease, vasculitis etc)
• The presence of hepatic disease (including hepatitis fatty liver or cirrhosis)
• The presence of renal disease (including azotemia or clinical proteinuria)
• The presence of cardiopulmonary disease (e.g. known asthma, cystic fibrosis, congenital heart disease)
• Individuals using medications which could affect sleep or breathing (including hypnotics)
• Individuals using chronic anti-inflammatory therapy
• Individuals with any subjects with acute or chronic illness.
• Individuals using anti-hypertensive therapies
• Children with a a BMI > 99.7%
• Adults with a BMI > 32 kg/m2

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CPAP; This arm will consist of patients with obstructive sleep apnea who will be asked to use CPAP nightly to treat their OSA for six months	Device: Continuous Positive Airway Pressure; This device delivers air pressure non invasively through a mask to stent open the upper airway to prevent obstruction during sleep. This is an FDA approved device that has been used for several decades to treat OSA.; Other Names: CPAP
Active Comparator: Diet and Exercise; This arm will consist of patients with obstructive sleep apnea who will be asked to engage in dietary management and regular exercise for six months.	Other: Diet And Exercise; This will consist of weekly telephone and monthly face to face visits to monitor and suggest measures to improve diet and regular exercise as conducted by a registered dietician.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peripheral Arterial Tonometry - Reactive Hyperemic Index	EndoPAT	At baseline.
Peripheral Arterial Tonometry - Reactive Hyperemic Index	EndoPAT	At three months.
Peripheral Arterial Tonometry - Reactive Hyperemic Index	EndoPAT	At six months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
miRNA 92a and miRNA 210 levels	Serum and Extracellular Vesicle derived miR 92a and miR 210 levels	At baseline.
miR 92a and miR 210 levels	Serum and Extracellular Vesicle derived miR 92a and miR 210 levels	At three months.
miR 92a and miR 210 levels	Serum and Extracellular Vesicle derived miR 92a and miR 210 levels	At six months.

Collaborators and Investigators

• Sponsor: University of California, San Diego

Publications and helpful links

General Publications

• Bhattacharjee R, Khalyfa A, Khalyfa AA, Mokhlesi B, Kheirandish-Gozal L, Almendros I, Peris E, Malhotra A, Gozal D. Exosomal Cargo Properties, Endothelial Function and Treatment of Obesity Hypoventilation Syndrome: A Proof of Concept Study. J Clin Sleep Med. 2018 May 15;14(5):797-807. doi: 10.5664/jcsm.7110.

Study record dates

Study Major Dates

• Study Start (Anticipated): April 1, 2019
• Primary Completion (Anticipated): July 30, 2024
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: May 21, 2018
• First Submitted That Met QC Criteria: June 1, 2018
• First Posted (Actual): June 6, 2018

Study Record Updates

• Last Update Posted (Actual): June 6, 2018
• Last Update Submitted That Met QC Criteria: June 1, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: Endothelial Dysfunction; Micro RNA
• 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
• Other Study ID Numbers: 170408

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Intellectual property and data generated under this project will be administered in accordance with both University and NIH policies, including the NIH Data Sharing Policy and Implementation Guidance of March 5, 2003.

As a part of this application will involve human subjects, investigators believe that the rights and privacy of people who will participate in the research project must be protected at all times. In case other investigators express interest in working with the data, every effort will be made to provide the data to them free of identifiers. However, such endeavors will have to be individually considered and also approved by the University of California (UC) San Diego Human Research Protection Program before any commitments can be made.

• IPD Sharing Time Frame: 5 years (during the study period)
• IPD Sharing Access Criteria: Only investigators that are listed as co-investigators with the UC San Diego Human Research Protection Program
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No