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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified November 2011 by Johns Hopkins University.
Recruitment status was  Recruiting
Sponsor:
Collaborator:
ResMed Foundation
Information provided by (Responsible Party):
Alan R. Schwartz, M.D., Johns Hopkins University
ClinicalTrials.gov Identifier:
NCT01482065
First received: November 15, 2011
Last updated: November 30, 2011
Last verified: November 2011
  Purpose

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.


Condition Intervention
Non Alcoholic Fatty Liver Disease
Obstructive Sleep Apnea
Device: CPAP (ResMed S9 autoset CPAP)

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: The Sleep, Liver Evaluation and Effective Pressure Study (SLEEP)

Resource links provided by NLM:


Further study details as provided by Johns Hopkins University:

Primary Outcome Measures:
  • Cross Sectional Analysis of NAFLD versus Sleep Apnea Severity Indices (AHI) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Liver Values and MR Indices [ Time Frame: 6 Months ] [ Designated as safety issue: No ]
    Serum ALT and AST activity and MR indices will be measured.

  • Analysis of Variance (ANOVA) in CPAP versus No-CPAP therapy on NAFLD [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 120
Study Start Date: November 2011
Estimated Study Completion Date: October 2013
Estimated Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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 6 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 AHI of 5-14.9, 15-29.9, and ≥ 30 events/hr, respectively.

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.
Other Name: ResMed S9 autoset CPAP

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 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.
  Eligibility

Ages Eligible for Study:   21 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥ 21
  2. Recent (≤ 12 months) liver biopsy
  3. Elevated levels of alanine aminotransferase (ALT) > 40, aspartate aminotransferase (AST) > 37, and alkaline phosphatase (ALKP) > 120

    • No other cause of liver disease other than NAFLD (as assessed by patient and physician surveys detailed below)

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 ≥ 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 vitamin E and pioglitazone or another glitazone or metformin
  17. Use of systemic steroids for > 10 days during prior 6 months
  18. Unstable cardiovascular disease (decompensated CHF, myocardial infarction or revascularization procedures, unstable arrhythmias)
  19. Uncontrolled hypertension with BP > 160/100
  20. Daytime hypoxemia with SaO2<90%
  21. Supplemental oxygen use
  22. Presence of any contraindication to MR examinations (see MRI Safety Screening Sheet)
  23. History of Metal in the Skull/Eyes
  24. Unable to have an MRI Scan
  25. Allergy or hypersensitivity reactions to gadolinium or any other ingredients, including benzyl alcohol
  26. Severe daytime hypersomnolence as defined by an Epworth Sleepiness Score of greater than 16.
  27. 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%.

Exclusions based on etiology of hepatitis will be assessed by querying both the hepatology list and patient about the above mentioned disorders (#7-15).

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01482065

Contacts
Contact: Michelle Guzman, RPSGT 410-550-2233 mguzman4@jhmi.edu

Locations
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21224
Contact: Michelle Guzman, RPSGT    410-550-2233    mguzman4@jhmi.edu   
Contact: Peter Grossman, B.S.    410-550-2380    pgrossm2@jhmi.edu   
Principal Investigator: Alan R Schwartz, M.D.         
Principal Investigator: Seva Polotsky, M.D., PhD         
Sponsors and Collaborators
Johns Hopkins University
ResMed Foundation
Investigators
Principal Investigator: Alan R Schwartz, M.D. Johns Hopkins University
  More Information

No publications provided

Responsible Party: Alan R. Schwartz, M.D., Medical Director, Sleep Disorders Center, Johns Hopkins University
ClinicalTrials.gov Identifier: NCT01482065     History of Changes
Other Study ID Numbers: NA_00048965, 111481
Study First Received: November 15, 2011
Last Updated: November 30, 2011
Health Authority: United States: Institutional Review Board

Keywords provided by Johns Hopkins University:
Non Alcoholic Fatty Liver Disease
NAFLD
Continuous Positive Airway Pressure
CPAP
CPAP Therapy
Apnea Hypopnea Index
AHI
Non alcoholic steatohepatitis
NASH
OSA
Obstructive Sleep Apnea

Additional relevant MeSH terms:
Apnea
Fatty Liver
Liver Diseases
Sleep Apnea Syndromes
Sleep Apnea, Obstructive
Respiration Disorders
Respiratory Tract Diseases
Signs and Symptoms, Respiratory
Signs and Symptoms
Digestive System Diseases
Sleep Disorders, Intrinsic
Dyssomnias
Sleep Disorders
Nervous System Diseases

ClinicalTrials.gov processed this record on July 24, 2014