The Sleep, Liver Evaluation and Effective Pressure Study

NCT ID: NCT01482065

Last Updated: 2017-01-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-11-30
• Study Completion Date: 2015-10-31

Brief Summary

This research is being done to examine: 1) how common obstructive sleep apnea (OSA) is in patients with non-alcoholic fatty liver disease (NAFLD), 2) whether the severity of OSA is related to the severity of NAFLD, and 3) whether treatment of OSA with continuous positive airway pressure (CPAP) improved NAFLD progression.

OSA is a condition caused by repetitive collapse of throat tissue during sleep that leads to falls in oxygen level and sleep disruption. OSA can be caused by obesity, and especially by fat found in the neck and belly.

NAFLD is a common disease linked to obesity. NAFLD is part of a disease spectrum, which can progress from steatosis (fatty liver) to nonalcoholic steatohepatitis (NASH), a progressive fibrotic disease, in which cirrhosis and liver-related death can occur. Recent evidence in patients with obstructive sleep apnea (OSA) indicates that OSA is associated with NASH. How common OSA is in patients with biopsy-confirmed NAFLD and the effect of OSA treatment with CPAP on NASH is unknown.

Detailed Description

Nonalcoholic fatty liver disease (NAFLD) is a common disease with a well-established link to obesity and is increasingly prevalent with the concurrent rise in obesity. NAFLD constitutes a disease spectrum from steatosis to cirrhosis and is associated with significant morbidity and mortality. The pathogenesis of NAFLD, especially disease progression, is not well understood. Obesity and insulin resistance play a role as 'a first hit' leading to liver steatosis, but the mechanisms for a 'second hit' triggering progression to steatohepatitis are not known. Based on our Preliminary Data, we propose a novel hypothesis that chronic intermittent hypoxia (CIH) in patients with obstructive sleep apnea (OSA) constitutes a 'second hit' causing progression of NAFLD from steatosis to nonalcoholic steatohepatitis (NASH), a progressive fibrotic disease, in which cirrhosis and liver-related death occur in up to 20% and 12% patients, respectively.

Obstructive sleep apnea (OSA) is characterized by recurrent collapse of the upper airway during sleep, leading to CIH. OSA is a common disease, present in 2% of women and 4% of men in the general US population, but with an increased prevalence of 30-60% in obese populations. Furthermore, CIH has been associated with multiple metabolic complications of OSA independent of obesity, including insulin resistance, dyslipidemia, and atherosclerosis. Previous work in rodent models has demonstrated that intermittent hypoxia (IH) increases: (1) insulin resistance; (2) hepatic steatosis; (3) hepatic levels of Sterol regulatory element-binding protein-1 (SREBP-1) and Stearoyl-CoA desaturase (SCD-1); and (4) hepatic oxidative stress and inflammation Thus, CIH in OSA may contribute to hepatic steatosis, and convert hepatic steatosis to steatohepatitis. To address this hypothesis, we will establish the impact of OSA on NASH in a susceptible cohort of obese human subjects in whom definitive intraoperative liver biopsy will be available to diagnose and stage NAFLD.

Recent evidence in patients with obstructive sleep apnea (OSA) indicates that OSA is associated with NASH. Nevertheless, the prevalence of OSA in patients with biopsy-confirmed NAFLD is unknown and the effect of OSA treatment with CPAP on NASH has never been studied. Our main hypothesis is that the severity of nocturnal intermittent hypoxemia of obstructive sleep apnea (OSA) will be associated with the severity of NAFLD. We will examine NAFLD severity in patients with and without obstructive sleep apnea and examine the effect of CPAP on NAFLD progression in patients with obstructive sleep apnea.

The overall goal is to determine whether OSA is associated with NAFLD and whether CPAP mitigates NAFLD progression. Our primary hypothesis is that the severity of nocturnal intermittent hypoxemia of obstructive sleep apnea (OSA) will be associated with the severity of NAFLD.

• In Specific Aim #1, we will examine NAFLD severity in patients with and without obstructive sleep apnea. We hypothesize that the severity of NAFLD and the presence of NASH will be associated with the presence and severity of OSA.
• In Specific Aim #2, we will examine the effect of CPAP on NAFLD progression in patients with obstructive sleep apnea. We hypothesize that CPAP will decrease markers of hepatic inflammation (serum aminotransferases) in patients with NAFLD, who have moderate or severe OSA. To address this hypothesis, we will enroll patients from the Johns Hopkins Medical Institution (JHMI) Hepatology clinic with the diagnosis of NAFLD, who have elevated serum aminotransferases, NAFLD on liver biopsy, and moderate to severe OSA. The effect of CPAP on markers of liver inflammation and serum aminotransferases will be determined, and related to CPAP adherence.

Conditions

Non Alcoholic Fatty Liver Disease; Obstructive Sleep Apnea

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

CPAP

Patients with moderate to severe apnea will be randomized to CPAP or deferred CPAP. Those in the CPAP group will be sent home with an autoset CPAP device, which they will be instructed to utilize for 4 months. The CPAP device will be set in the "auto mode" so that it will automatically adjust the pressure at night to eliminate upper airway obstruction during sleep.

Criteria for OSA severity are specifically designed to target patients with nocturnal hypoxemia, which is hypothesized to contribute to NAFLD progression. According to the guidelines of the American Academy of Sleep Medicine, apnea will be defined as cessation of airflow for ≥ 10 sec. and hypopnea will be defined as decreased airflow for ≥ 10 sec. leading to oxyhemoglobin desaturation ≥ 4%. Mild, moderate and severe OSA will be diagnosed by an Apnea-Hypopnea Index (AHI) of 5-14.9, 15-29.9, and ≥ 30 events/hr, respectively.

Group Type: EXPERIMENTAL

CPAP (ResMed S9 autoset CPAP)

Intervention Type: DEVICE

A ResMed S9 autoset CPAP device will be utilized throughout the study. Throughout the study intervention period, subjects (for AHI\> 15) will be instructed to utilize their CPAP and adherence will be monitored using an automatic meter that is built into the CPAP device.

Interventions

CPAP (ResMed S9 autoset CPAP)

A ResMed S9 autoset CPAP device will be utilized throughout the study. Throughout the study intervention period, subjects (for AHI\> 15) will be instructed to utilize their CPAP and adherence will be monitored using an automatic meter that is built into the CPAP device.

Intervention Type: DEVICE

Other Intervention Names

ResMed S9 autoset CPAP

Eligibility Criteria

Inclusion Criteria

• Age ≥ 21
• Diagnosis of NAFLD and BMI ≥ 30 or obesity with BMI > 35 and < 400lbs
• No other cause of liver disease other than NAFLD (as assessed by patient and physician surveys detailed below, blood work and magnetic resonance imaging(MRI))

Exclusion Criteria

Both patients and doctors will be asked to identify potential exclusionary conditions including:

1. Patients with sickle cell anemia, hemoglobinopathies and other hemolytic anemias

2. Known clinical hypersensitivity or a history of asthma or allergic respiratory disorders

3. Advanced renal failure (currently requiring dialysis or with a Glomerular Filtration rate < 30cc/min)

4. Pregnancy

5. History of CPAP treatment for OSA

6. Recent weight loss (6 months) ≥ 10%

7. Current alcohol use > 20 g/day in women and > 30 g/day in men, or prior use for ≥ 3 consecutive months during the previous 5 years as assessed with the Lifetime Drinking History Questionnaire Viral hepatitis A, B and C

8. Autoimmune hepatitis

9. Hemochromatosis

10. Wilson's disease

11. Alpha-1-antitrypsin deficiency

12. Primary sclerosing cholangitis

13. Cirrhosis of any etiology

14. History of HIV infection and/or HAART therapy

15. Evidence of drug-induced liver injury

16. Use of systemic steroids for > 10 days during prior 6 months

17. Unstable cardiovascular disease (decompensated chronic heart failure (CHF), myocardial infarction or revascularization procedures, unstable arrhythmias)

18. Uncontrolled hypertension with BP > 190/110

19. Daytime hypoxemia with oxygen saturation (SaO2)<90%

20. Supplemental oxygen use

21. Presence of any contraindication to MR examinations (see MRI Safety Screening Sheet)

22. History of Metal in the Skull/Eyes

23. Unable to have an MRI Scan

24. Severe daytime hypersomnolence as defined by an Epworth Sleepiness Score of greater than 10.

25. Severe sleep apnea as characterized by an apnea-hypopnea index of greater than 80 episodes/hour or an average low SaO2 during sleep disordered breathing episodes below 80%.

26. Work in transportation industry as a driver or pilot.

27. Patients with a diagnosis of sleep apnea on active treatment.

Exclusions based on etiology of hepatitis will be assessed by querying both the hepatology list and patient about the above mentioned disorders (#7-15) and through testing for viral hepatitis A, B, C, ferritin, antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), anti-mitochondrial antibody, anti-smooth muscle antibody and ceruloplasmin.

• Minimum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

ResMed Foundation

OTHER

Sponsor Role: collaborator

Johns Hopkins University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Alan R Schwartz, M.D.

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

Locations

Johns Hopkins University

Baltimore, Maryland, United States

Countries

United States

Other Identifiers

111481

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

NA_00048965

Identifier Type: -

Identifier Source: org_study_id