E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with Non-Alcoholic Fatty Liver Disease |
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E.1.1.1 | Medical condition in easily understood language |
Patients having a liver disease called Non-Alcoholic Fatty Liver Disease, which is a disease that affects the liver. |
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E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to develop an algorithm based on OBT with or without MBT with or without additional clinical and/or laboratory parameters, and its cut-off to correlate with histological findings, as assessed by a central reader, of NAFLD. |
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E.2.2 | Secondary objectives of the trial |
The secondary objective of the study is to assess correlation between OBT with or without MBT with or without other available biomarkers and disease course, defined by clinical outcomes, at 18 and 36 months.
Safety will be assessed by assessing all adverse and serious adverse events occurring in all subjects enrolled from the time of enrollment until the subject completes the protocol. Any AEs reported that are possibly or probably related to the use of the product or related to the procedure within 36 months post last breath test performed or until subject termination will be followed until resolution and if laboratory work is done secondary to AEs and found abnormal, these tests will be followed until normalization or stabilization.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Adult men or women (≥18 years of age) 2. Liver biopsy, indicated to rule-out or confirm NAFLD, performed within 6 months prior to or 1 month after both breath-tests NOTE: The samples obtained must meet pre-defined quality criteria as an inclusion criterion. (See Appendix II for biopsy quality requirements) OR: Undergoing Liver biopsy to rule-out or confirm NAFLD/NASH. 3. No other known co-existent liver disease, excluded by appropriate serologic / other testing 4. Patient able and willing to sign an Informed Consent Form 5. Can tolerate an overnight (8-hour) fast
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E.4 | Principal exclusion criteria |
1. Positive studies for any of the following within three years prior to biopsy: * Anti HCV positive * Anti HBsAg positive * Iron saturation > 60% + gene test for hereditary hemochromatosis or iron overload as defined by presence of 3+ or 4+ stainable iron on liver biopsy * Antinuclear antibody at a titer > 1: 160 along with hypergammaglobulinemia and 5 times ALT normal levels * Alpha-1-antitrypsin level below lower limit of normal (< 150 mg/dl) or no PAS diastase resistant globules on biopsy. * 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 * Low level of ceruloplasmin (< 10 gn/mL) * Drug-induced liver disease as defined on the basis of typical exposure and history Note: These studies do not need to be performed if they are not available, as it is assumed that if they are not on file, the condition does not exist 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 that 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: Octanoate or Methacetin and their metabolites, i.e. paracetamol, acetaminophen 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 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 trans-jugular intrahepatic porto-systemic shunt (TIPS) according to initial imaging studies.
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E.5 End points |
E.5.1 | Primary end point(s) |
Correlation of histological findings, as assessed by a central reader, of NAFLD compared to 13C-Octanoate Breath Test with or without 13C-Methacetin Breath Test with or without additional clinical and/or laboratory parameters. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The correlation will be evaluated when the patient will have undergone the two respiratory tests (the two tests are done once the patient is enrolled, and are separated of at least 48 hours and no more than 30 days). The 2 tests, to be compared to the histological findings, will be done no more than 6 months after the biopsy they are compared to. |
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E.5.2 | Secondary end point(s) |
Correlation between OBT ± MBT and clinical course (i.e. clinical outcome: liver decompensation events etc.) at 18 and 36 months post the last breath test performed (visit/phone). NOTE: Patients undergoing intervention for NASH / NAFLD, including both approved and experimental approaches prior to the defined time points will be terminated hence will not be evaluated for this endpoint.
Safety will be assessed by reviewing all adverse and serious adverse events occurring in all subjects enrolled from the time of enrollment until the subject completes the protocol. Any AEs reported that are possibly or probably related to the use of the product or related to the procedure within 36 months post last breath test performed or until subject termination will be followed until resolution and if laboratory work is done secondary to AEs and found abnormal, these tests will be followed until normalization or stabilization. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondray endpoints will be evaluated at 18 and 36 months post the last breath test performed.
Any AEs reported that are possibly or probably related to the use of the product or related to the procedure within 36 months post last breath test performed or until subject termination will be followed until resolution and if laboratory work is done secondary to AEs and found abnormal, these tests will be followed until normalization or stabilization. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | Yes |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Histological findings, from a liver biopsy the patient will have undergone prior to the study |
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E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
France |
Italy |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 1 |