The Sleep, Liver Evaluation and Effective Pressure Study

Obstructive Sleep Apnea Clinical Trial

— SLEEP  

Official title:

The Sleep, Liver Evaluation and Effective Pressure Study (SLEEP)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01482065
• Other study ID #: NA_00048965
• Secondary ID: 111481
• Status: Active, not recruiting
• Phase: N/A
• First received: November 15, 2011
• Last updated: April 7, 2015
• Start date: November 2011
• Est. completion date: October 2015

Study information

• Verified date: April 2015
• Source: Johns Hopkins University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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 SREBP-1 and 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 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 120
• Est. completion date: October 2015
• Est. primary completion date: October 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 21 Years and older

Eligibility

IInclusion 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 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 CHF, myocardial infarction or revascularization procedures, unstable arrhythmias)

18. Uncontrolled hypertension with BP > 190/110

19. Daytime hypoxemia with 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, ANA, ANCA, anti-mitochondrial antibody, anti-smooth muscle antibody and cerulloplasmin.

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Fatty Liver
• Liver Diseases
• Non Alcoholic Fatty Liver Disease
• Obstructive Sleep Apnea
• Sleep Apnea, Obstructive

Intervention

Device:
• 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.

Locations

Country	Name	City	State
United States	Johns Hopkins University	Baltimore	Maryland

Sponsors (2)

Lead Sponsor	Collaborator
Johns Hopkins University	ResMed Foundation

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cross Sectional Analysis of NAFLD versus Sleep Apnea Severity Indices (AHI)	Cross-sectional analysis will be performed in NAFLD study participants from the JH Hepatology Clinic to examine the relationship between findings on liver biopsy and sleep apnea severity indices. The main predictor variable will be presence/severity of OSA and nocturnal oxyhemoglobin desaturation (assessed by T90%, time w/ oxyhemoglobin desaturation < 90%; Delta SaO2 between baseline and minimal oxyhemoglobin saturation, and standard deviation of nocturnal SaO2). Our primary outcome will be NAFLD activity score on biopsy.	6 months	No
Secondary	Liver Values and MR Indices	Serum ALT and AST activity and MR indices will be measured.	6 Months	No
Secondary	Analysis of Variance (ANOVA) in CPAP versus No-CPAP therapy on NAFLD	we will test our hypothesis that CPAP therapy improves NAFLD. The main independent variables will be CPAP vs. deferred-CPAP therapy. In a subanalysis, responses in the CPAP treatment group will be compared based on compliance. Compliance with CPAP is defined as using it on > 70% of the days, at least 4 h per night. Our primary outcome will be serum activity of ALT and AST. We will use ANOVA to examine changes in ALT and AST depending on CPAP therapy group and compliance. Secondary outcomes will include the degree of hepatic steatosis and fibrosis, as assessed by MR.	6 months	No