E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Nonalcoholic Fatty Liver Disease (NAFLD) or Nonalcoholic Steatohepatitis (NASH) |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 22.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10029530 |
E.1.2 | Term | Non-alcoholic fatty liver |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 22.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10053219 |
E.1.2 | Term | Non-alcoholic steatohepatitis |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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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 |
To assess the safety and tolerability of 13 weeks of treatment with FM101 in patients with nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH)
To assess the treatment effect of FM101 on serum alanine aminotransferase (ALT) concentrations after 13 weeks of treatment
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E.2.2 | Secondary objectives of the trial |
To assess the effect of 13 weeks of treatment with FM101 on the change in liver stiffness (kPa) measured by magnetic resonance imaging- (MRI)-magnetic resonance elastography (MRE) in patients with NAFLD or NASH
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Be able and willing to provide written informed consent to take part in the study and to comply with all the study’s requirements. 2. Be a man or woman ≥18 years of age at screening. 3. Have a. Histologic confirmation of NASH no more than 12 months before the screening visit date, demonstrating the existence of steatosis ≥5%, hepatocyte ballooning and chronic inflammation (at least 1 point for each component), and stage 1 through stage 3 liver fibrosis according to the NASH Clinical Research Network (CRN); OR b. NAFLD based upon demonstration of at least 3 of the following 5 components of the metabolic syndrome below, at screening: • FPG ≥100 mg/dL (≥5.6 mmol/L), or undergoing drug treatment for elevated plasma glucose concentrations • HDL-C concentration <40 mg/dL in male patients, or <50 mg/dL in female patients, or undergoing drug treatment for reduced serum HDL-C concentrations • Serum triglyceride (TG) concentration ≥150 mg/dL, or undergoing drug treatment for elevated serum TG concentrations • Waist circumference >102 cm in male patients or >88 cm in female patients • Systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥85 mm Hg, or undergoing drug treatment for hypertension, or antihypertensive drug treatment in a patient with a history of systemic hypertension 4. Serum ALT concentration >1 × ULN at screening 5. FIB-4 result >1.3 and ≤3.25, at screening: • If the FIB-4 result is ≥1.3 but ≤1.45, OR >2.67 and ≤3.25, the patient must undergo Fibroscan (VCTE) before proceeding to MRI studies. • The Fibroscan (VCTE) result must be >4 kPa but ≤12.5 kPa. • If such a Fibroscan (VCTE) result exists from the 3-month period before screening visit date, this result may be used. 6. Undergo MRI-PDFF that demonstrates ≥8% liver steatosis during the screening period. 7. Undergo MRI-MRE with a score ≥2.9 kPa during the screening period. 8. WOCBP must have a negative serum β-human chorionic gonadotropin test result at screening. Female patients must agree to use at least 1 highly effective birth control throughout the study and up to 30 days after the last dose of study drug has been taken. Highly effective contraception measures include the following options, but are not limited to: • Combined estrogen- and progestogen-containing hormonal contraception (administration may be oral, intravaginal, or transdermal); • Progestogen-only hormonal contraception associated with inhibition of ovulation (administration may be oral, injectable, or implantable); • Intrauterine device, intrauterine hormone-releasing system, bilateral tubal, occlusion (‘tubal occlusion’ includes ‘tubal ligation’); • Vasectomized partner (provided that the male has provided confirmation of surgical success and in the event that the vasectomized partner is the sole sexual partner of the woman of childbearing potential); • Sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk in relation to the duration of the clinical trial), only in the event that this is the preferred lifestyle of the patient. Childbearing potential is defined as being fertile after menarche and until becoming postmenopausal unless permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy). A postmenopausal state is defined as no menses for ≥12 consecutive months without an alternative medical cause. Men with partners who are WOCBP must either be surgically sterile or agree to use a barrier contraceptive for the duration of the study and up to 30 days after the last dose of study drug. 9. Be willing to maintain a stable diet, including alcohol intake where this applies, and physical activity levels throughout the entire study.
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E.4 | Principal exclusion criteria |
1. Any patient who refuses to provide written informed consent to take part in the study, and/or appears unwilling to comply with study-specific requirements 2. Female persons who are pregnant or are breastfeeding at screening, or who plan to become pregnant during the study 3. BMI <25 kg/m2 4. Any of the laboratory test abnormalities at screening (see the list in the protocol section 8.2 Exclusion Criteria) 5. Chronic liver disease other than confirmed NASH or NAFLD, including but not limited to the diagnoses/entities (see the list in the protocol section 8.2 Exclusion Criteria) 6. Medical, histologic, and/or imaging history of hepatic cirrhosis 7. Clinical, endoscopic, imaging and/or laboratory manifestations of portal hypertension, such as spider nevi, splenomegaly, clinically evident ascites formation, nonbleeding gastro-oesophageal varices 8. Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) related illness 9. Chronic use (≥12 months) of any drug known to be associated with development of NAFLD during the 5 years before the anticipated Day 1 visit date (eg, amiodarone, methotrexate, systemic glucocorticoids [unless employed at physiologic replacement doses for management of confirmed adrenal insufficiency], tetracyclines, tamoxifen, estrogens at doses greater than those used for hormone replacement therapy, anabolic steroids [other than testosterone replacement preparations being taken at a physiologic replacement dose for management of confirmed male hypogonadism], sodium valproate, and other hepatotoxins such as minocycline) 10. Use of the medications (see the list in the protocol section 8.2 Exclusion Criteria) 11. History of significant alcohol consumption, defined as an average of >20 g/day in female patients and >30 g/day in male patients, for a period of >3 consecutive months within 1 year before screening, hazardous alcohol use (Alcohol Use Disorders Identification Test score ≥8), or an inability to reliably quantify alcohol consumption based upon judgment of the investigator 12. Use of legally prohibited substance or substances within 1 year before the screening visit date in a manner that may jeopardize the patient’s willingness and/or ability to complete study requirements, in the judgment of the investigator. 13. Weight change ≥7% within the 6 months before screening or ≥5% within the 3 months before screening 14. Prior or planned (during the study period) weight reduction surgery (eg, sleeve gastrectomy, Roux-en-Y gastrojejunostomy) 15. Type 1 diabetes mellitus by medical history 16. Poorly controlled type 2 diabetes mellitus (this is defined as HbA1c >9.5% at screening, or a patient whose oral antidiabetic medication dosing requires adjustment >10% less than 2 months before the screening visit date). 17. Uncontrolled systemic hypertension (either treated or untreated) defined as systolic blood pressure >160 mm Hg or a diastolic blood pressure >100 mm Hg at screening. A retest of blood pressure, (after establishing good blood pressure control within a reasonable period of time and up to the Baseline visit) is permissible at the discretion of the investigator 18. Patients who demonstrate recent evidence (within 6 months of the anticipated date of the Day 1 visit) of clinically evident and significant atheromatous cardiovascular disease (eg, unstable angina, acute coronary syndrome, myocardial infarction, cerebrovascular accident [stroke], cerebrovascular ischemia, transient ischemic attack, and / or peripheral vascular disease requiring intervention) 19. Has taken part in a clinical trial and been administered an active investigational product being evaluated for the treatment of NASH, weight reduction and / or type 2 diabetes mellitus, during the 6 months before the anticipated Day 1 visit date 20. Has participated in an investigational new drug trial during the 30 days before screening visit date, or within 5 half-lives of an investigational agent, whichever is longer 21. Has a confirmed diagnosis of malignancy within 5 years before screening, except for basal or squamous cell carcinoma of the skin that has been treated successfully or cervical carcinoma in situ that has been treated successfully. Patients with a history of other malignancies that have been treated with curative intent and who have no demonstrable disease recurrence within 5 years before screening may also be eligible if approved after discussion with the sponsor’s medical monitor. Patients under evaluation for malignant disease currently are not eligible for study participation. 22. Patients who are unable to undergo MRI studies, whatever the reason for this 23. Any other condition that, in the opinion of the investigator, would impede compliance with, hinder completion of the study, compromise the well-being of the patient, and / or interfere with the study’s endpoints. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Number and percentage of patients with TEAEs, related TEAEs, and/or severe TEAEs [Time Frame: From administration of FM101 on Day 1 to the last follow up visit] 2. Change from Baseline to postbaseline assessments during 13 weeks of treatment in serum ALT concentrations
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Time Frame: From administration of FM101 on Day 1 to the last follow up visit 2. during 13 weeks |
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E.5.2 | Secondary end point(s) |
Changes from Baseline to Week 13 in liver stiffness (kPa) on MRE. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | |
E.8.9.1 | In the Member State concerned months | 26 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 26 |