Non-Alcoholic Steatohepatitis
Conditions
Brief summary
This study's aim is to develop an algorithm for the ¹³C-Octanoate Breath Test with or without the ¹³C-Methacetin Breath Test (OBT and MBT respectively) for correlation with histological findings associated with of Non-Alcoholic Steatohepatitis (NASH) and other liver diseases using the BreathID® System
Detailed description
Non-Alcoholic Steatohepatitis (NASH) is a growing epidemic in the western world due to the contemporary eating habits and life styles.NASH can lead to cirrhosis, hepatic carcinoma and other liver complications. There are currently some treatments available. The only definitive way of detecting NASH in patients with advanced liver disease is by liver biopsy. However, liver biopsy has disadvantages, such as sampling errors, chance of complications and does not lend itself to following up after treatment. A non-invasive test that could potentially replace biopsy and aid in NASH detection and treatment monitoring, would improve management of suspected NASH patients without the need for biopsy. This protocol will obtain the results of one or two different breath tests to provide an accurate evaluation of the liver status in patients at high risk for NASH.
Interventions
DEVICESuspected NASH BreathID test with 13C-Octanoate
Subject will have breath measured before and after ingestion of solution of 100 mg 13C Octanoate dissolved in 150 cc of water
DEVICESuspected NASH Breath test with 13C Methacetin
Subject will have breath measured before and after ingestion of solution of 75 mg 13C Methacetin dissolved in 150 cc of water
Sponsors
Meridian Bioscience, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adult men or women (≥18 years of age) 2. Liver biopsy, indicating NAFLD/NASH, performed within 6 months prior to both breath tests OR undergoing liver biopsy to rule-out or confrim NAFLD/NASH. NOTE:The samples obtained meet defined quality criteria. (In Appendix II of protocol) 3. Any elevation of liver enzymes above the upper limit of normal (any or all of the following: AST, ALT, GGT, Alkaline phosphatase) for at least 3 months 4. No other known co-existent liver disease, excluded by appropriate serologic / other testing 5. Imaging - US / CT / MRI (if available) with the typical image of Fatty Liver or suggestive of NASH. 6. Patient (or legal guardian) able and willing to sign an Informed Consent Form 7. Can tolerate an overnight (8-hour) fast
Exclusion criteria
1. Positive studies for any of the following within three years prior to biopsy: 1. Anti HCV positive 2. Anti HB core antibody positive 3. Iron saturation \> 60% + gene test for hereditary hemochromatosis or iron overload as defined by presence of 3+ or 4+ stainable iron on liver biopsy 4. Antinuclear antibody at a titer \> 1: 160 along with hypergammaglobulinemia and 5 times ALT normal levels 5. Alpha-1-antitrypsin level below lower limit of normal (\< 150 mg/dl) or no PAS diastase resistant globules on biopsy. 6. Primary biliary cirrhosis as defined by elevation of alkaline phosphatase greater than upper limit of normal and anti-mitochondrial antibody (AMA) of greater than 1:80 and consistent liver histology 7. Low level of ceruloplasmin 8. Drug-induced liver disease as defined on the basis of typical exposure and history 2. Patients known to have chronic liver disease other than NAFLD as routinely diagnosed by the investigator 3. Concurrent acute hepatic condition other than NAFLD 4. Alcohol consumption \> 20 gm/day (0.71 oz/day) for women and \> 30 gm/day (1.06 oz/day) for men 5. Drugs that may interfere with octanoate metabolism or can also cause NAFLD independent of the metabolic syndrome, including: corticosteroids, amiodarone, tetracycline, valproic acid, methotrexate, stavudine, zidovudine 6. When MBT is performed subject should not have taken any of the following at least 48 hours prior to the breath test: Acyclovir , allopurinol, carbamazepine, cimetidine, ciprofloxacin, daidzein, (herbal) disulfiram, echinacea, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, montelukast, norfloxacin, phenylpropanolamine, phenytoin, propafenone, rifampin, terbinafine, ticlopidine, thiabendazole, verapamil, zileuton or any medication that might interfere with Methacetin metabolism or might affect CYP 1A2 7. Patients that have had more than 10% weight change between biopsy and enrollment. 8. Hypersensitivity to any of the study substrates; i.e. Octanoate or Methacetin respectively 9. Known extra-hepatic diseases including but not limited to: severe congestive heart failure (NIHA\>2), known severe pulmonary hypertension (\>35 mmHg), history of chronic obstructive pulmonary disease or uncontrolled symptomatic bronchial asthma or uncontrolled diabetes mellitus (HA1c\>9.5%) 10. Previous surgical GI bypass surgery 11. Extensive small bowel resection (\>100 cm) 12. Known uncontrolled malabsorption or diarrhea 13. Concurrent total parenteral nutrition 14. Any organ transplant 15. Patients receiving any anti-viral treatment or any other liver directed therapy, procedure or surgery between the time of the biopsy and the breath test 16. Pregnant or breast feeding 17. Patients and/or legal guardian unable or refusing to sign informed consent 18. Patients that, based on the opinion of the investigator, should not be enrolled into this study due to safety / adherence reasons. 19. Patients participating in other clinical trials and already receiving experimental treatments or procedures 20. Patients with suspected or documented hepatocellular carcinoma by ultra-sound or other imaging modality 21. Patients diagnosed with partial / complete portal venous occlusion, hepatic venous occlusion, previous PHT surgery, or placement of a transjugular intrahepatic portosystemic shunt (TIPS) according to initial imaging studies.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Biopsy Proven Non-Alcoholic Steatohepatitis | 30 days | Non-Alcoholic Steatohepatitis (NASH) as determined by liver biopsy histology will be the comparator |
| Liver Decompensation as Measured by Area Under Receiver Operating Curve | 36 months | Observe if breath tests correlate to clinical outcome of liver decompensation, including ascites, variceal bleeding, hepatic encephalopathy and spontaneous bacterial peritonitis. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | 48 hours from last breath test | A phone call will be made to each subject 48 hours after the last breath test to confirm that no adverse events related to breath test have been experienced. |
Countries
Belgium, France, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Suspected NASH 13C-Octanoate, 13C-Methacetin
Suspected NASH BreathID test with 13C-Octanoate: Subject will have breath measured before and after ingestion of solution of 100 mg 13C Octanoate dissolved in 150 cc of water
Suspected NASH Breath test with 13C Methacetin: Subject will have breath measured before and after ingestion of solution of 75 mg 13C Methacetin dissolved in 150 cc of water | 135 |
| Total | 135 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol Violation | 28 |
Baseline characteristics
| Characteristic | Suspected NASH |
|---|---|
| Age, Continuous | 53.4 years STANDARD_DEVIATION 12.57 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 29 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 106 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Region of Enrollment Belgium | 15 participants |
| Region of Enrollment France | 9 participants |
| Region of Enrollment United Kingdom | 9 participants |
| Region of Enrollment United States | 102 participants |
| Sex: Female, Male Female | 75 Participants |
| Sex: Female, Male Male | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 135 |
| other Total, other adverse events | 5 / 135 |
| serious Total, serious adverse events | 1 / 135 |
Outcome results
Primary
Liver Decompensation as Measured by Area Under Receiver Operating Curve
Observe if breath tests correlate to clinical outcome of liver decompensation, including ascites, variceal bleeding, hepatic encephalopathy and spontaneous bacterial peritonitis.
Time frame: 36 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Suspected NASH | Liver Decompensation as Measured by Area Under Receiver Operating Curve | 0.852 Probability |
Primary
Number of Participants With Biopsy Proven Non-Alcoholic Steatohepatitis
Non-Alcoholic Steatohepatitis (NASH) as determined by liver biopsy histology will be the comparator
Time frame: 30 days
Population: Subjects that had a valid biopsy and performed both Octanoate and Methacetin Breath test
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Suspected NASH | Number of Participants With Biopsy Proven Non-Alcoholic Steatohepatitis | Definite NASH | 74 Participants |
| Suspected NASH | Number of Participants With Biopsy Proven Non-Alcoholic Steatohepatitis | Probable NASH | 20 Participants |
| Suspected NASH | Number of Participants With Biopsy Proven Non-Alcoholic Steatohepatitis | Absent of NASH | 13 Participants |
Other Pre-specified
Number of Participants With Adverse Events
A phone call will be made to each subject 48 hours after the last breath test to confirm that no adverse events related to breath test have been experienced.
Time frame: 48 hours from last breath test
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Suspected NASH | Number of Participants With Adverse Events | Possibly related adverse event | 0 Participants |
| Suspected NASH | Number of Participants With Adverse Events | No possibly related reported adverse events | 135 Participants |