| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis |
|
| E.1.1.1 | Medical condition in easily understood language |
| cirrhosis caused by non-alcoholic fatty liver disease |
|
| 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 | 24.1 |
| 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 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064844 |
| E.1.2 | Term | Compensated cirrhosis |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| 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 this study is to evaluate the efficacy and safety of aldafermin compared to placebo. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of this study are to evaluate the efficacy of aldafermin and the effect of aldafermin on pharmacokinetics and on biomarkers of target engagement, fibrogenesis and imaging. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The optional Pharmacokinetics (PK) sub-study
For the subjects in the optional PK sub-study, the serum PK of aldafermin will be summarized by estimation of total exposure (AUC), maximum observed serum concentration (Cmax), clearance (Cl/F), volume of distribution (Vz/F) and terminal half-life (T1/2) on the basis of results obtained. Estimates for these PK parameters will be tabulated and summarized by descriptive statistics (mean, standard deviation, median, minimum and maximum, geometric mean and geometric coefficient of variation). An exploratory analysis of the potential relationship between PK and other endpoints (e.g., safety, PD biomarkers) may be conducted. Additional PK analyses and/or summary statistics will be conducted as appropriate. |
|
| E.3 | Principal inclusion criteria |
1. Males and females between 18 and 75 years of age, inclusive, who are able to comprehend and willing to sign an Informed Consent Form (ICF).
2. Liver biopsy consistent with a diagnosis of NASH Cirrhosis according to NASH CRN criteria and per the central pathologist evaluation.
a. A historical biopsy is acceptable if tissue slides are available from within 12 months prior to Screening and are acceptable for the central pathologist evaluation.
b. Liver biopsies must be consistent with cirrhosis according to the NASH CRN classification (NASH CRN fibrosis score of 4), as assessed by the central reader (see also Inclusion Criterion 4).
c. NASH must be the etiology of cirrhosis (i.e., no other causes of cirrhosis; see also Inclusion Criterion 4)
d. A limited number of subjects (capped at 10% of planned enrollment) with clinical diagnosis of NASH cirrhosis may be enrolled despite a NASH CRN fibrosis score of 3.(please refer to Protocol)
3. Criterion deleted per Protocol Version 5.0
4.Subjects must have Definitive NASH cirrhosis as defined in Noureddin 2020. (refer to Protocol)
5. AFP ≤ 20 ng/mL at Screening.
6. Negative for hepatic lesions/nodules indicating HCC risk
a. MRI is the preferred imaging modality. There must be no nodules with a Liver Imaging and Reporting Data System (LI-RADS) score of ≥ 2 by central radiologist evaluation.
b. If MRI is not available or not possible to be performed, a multi-phasic CT scan may be used to assess HCC risk. There must be no nodules with
a LI-RADS score ≥ 2 by central radiologist evaluation.
c. If MRI and CT are not available or not possible to be performed for screening a potential subject, then ultrasonography of the liver may be performed:
1) If no hepatic lesions or nodules (local radiologist evaluation) and AFP ≤ 20 ng/mL, the potential subject may be considered further for enrollment.
2) For any findings of hepatic lesions or nodules (local radiologist
evaluation) that are not clearly benign cysts and have not been shown clearly benign by prior CT or MRI, follow up MRI must be performed and meet criteria (no nodules with LI-RADS score of ≥ 2 evaluated centrally) in order for the potential subject to be considered further for enrollment.
7. Subjects with Type 2 Diabetes (T2D) or insulin resistance are permitted as long as diabetic medications are reasonably stable within 3 months prior to Screening, as outlined in Section 6.4.
8. Other concomitant medications/therapies used for the treatment of coexisting conditions (Section 6.4) are acceptable but require a stable regimen for at least 3 months prior to the Screening except for non-statin lipid lowering agents, which can be used until Da1 of
Screening.
9. Statin use is acceptable based on the following criteria, as assessed by the investigator at Screening:
a. Statin-naïve is defined as no administration of statins within 3 months prior to Screening.
b. Statin-Experienced is defined as currently receiving ≤ 50% of the maximal approved dose of statin therapy
i. Requires a reasonably stable statin dosing at least 3 months prior to Screening
10. The following additional laboratory parameters must be met at Screening:
a. Total bilirubin ≤ 1.3 mg/dL
i. If Gilbert's Syndrome, direct bilirubin within ULN.
b. HbA1c ≤ 9.5%.
c. Platelet count ≥ 120,000/mm3. Subjects who meet the Baveno VI criteria with a platelet count >110,000/mm3 and <120,000/mm3 may be enrolled if they meet the expanded Baveno VI criteria (Note: No more than 30% of the remaining population will be enrolled using the Baveno VI criteria).
d. Creatinine clearance ≥ 60 mL/min as calculated by Cockcroft-Gault equation.
e. Serum alanine amino transferase (ALT) levels ≤ 5X upper limit of normal (ULN).
f. Serum aspartate amino transferase (AST) levels ≤ 5X ULN.
g. Alkaline phosphatase ≤ 1.5X ULN.
h. Serum albumin ≥3.5 g/dL.
i. International normalized ratio (INR) ≤1.7.
11. Female subjects must be either of a) non-childbearing potential, defined as women who have had a hysterectomy, bilateral oophorectomy, medically documented ovarian failure, documented postmenopausal, or a follicle stimulating hormone ≥ 40 mIU/mL, OR b) if of childbearing potential, defined as including women < 55 years of age with ≤ 2 years of amenorrhea (absence of menstruation and not due to any reversible medical cause or any current medication use), then have a negative serum pregnancy test at Screening and urine pregnancy test at the Day 1 visit prior to first dose of study drug, and be nonlactating and non-breastfeeding. Note: Females who do not meet this criterion can be included if they meet inclusion criterion 12.
12. Female subjects of childbearing potential and male subjects with a female partner of childbearing potential must agree to consistent and adequate birth control from Screening to EOS (Week 54). |
|
| E.4 | Principal exclusion criteria |
1. Other causes of liver disease that are primary, secondary, or otherwise causes of cirrhosis or which may confound the intended patient population according to the investigator, including but not limited to alcoholic liver disease, hepatitis B, hepatitis C, autoimmune disorders, primary biliary cirrhosis, drug-induced hepatotoxicity, Wilson’s disease, hemochromatosis, and alpha-1-anti-trypsin deficiency based on medical history and/or centralized read of liver histology.
2. Evidence of drug induced steatohepatitis secondary to amiodarone, corticosteroids, estrogens, methotrexate, tetracycline, or other medications known to cause hepatic steatosis.
3. History of hepatic decompensation, including: variceal bleeding, ascites, or hepatic encephalopathy.
4. Prior or pending liver transplantation.
5. Child Pugh class B and C status.
6. Model of end stage liver disease (MELD) score > 12.
7. Evidence of worsening liver disease (defined below) between screening visits (i.e. Day -56 and Day -42) including measures of AST, ALT, alkaline phosphatase (ALP) or total bilirubin (TBL):
8. History of porto-systemic shunt procedure.
9. No evidence of gastroesophageal varices as documented by one of the following assessments:
a. A historical and locally evaluated EGD obtained within 365 days of screening or
b. A locally evaluated EGD conducted during the screening period
10. Clinically significant cardiovascular or cerebrovascular event or new diagnosis within 6 months of Screening, including but not limited to congestive heart failure, myocardial infarction, acute coronary syndrome, revascularization, stroke (hemorrhagic or ischemic), transient ischemic attack (TIA), or implanted defibrillator or pacemaker (for uncomplicated elective, non-biventricular pacemaker procedure, 3 months post procedure will be allowed).
11. Gastric bypass or bariatric surgery in the past 5 years or planned procedure during the study period.
12. History of clinically significant unstable or untreated illness or any other major medical disorder that may interfere with subject treatment, assessment, or compliance with the protocol.
13. Documented significant weight change (± 5%) < 3 months prior to Screening.
14. Screening ECG with clinically significant abnormalities that in the investigator's opinion, require evaluation and possible treatment.
15. Positive for HBsAg, antiHIV Ab, or antiHCV Ab plus HCV-RNA. Subjects who are antiHCV Ab- positive but HCV-RNA negative (secondary to treatment or viral clearance) are eligible with at least a 1-year period since documented sustained viral response at Week 12 post-treatment.
16. History of malignancy diagnosed or treated within 2 years (recent localized treatment of squamous or non-invasive basal cell skin cancers is permitted; cervical carcinoma in situ or breast ductular carcinoma in situ is allowed if appropriately treated within 2 years prior to Screening); subjects under evaluation for suspected malignancy are not eligible. History of hepatocellular carcinoma at any point regardless of treatment or treatment success will be excluded.
17. A positive drug screen (e.g., morphine, heroin, cocaine) will exclude subjects unless it can be clearly explained by a prescribed medication. The diagnosis and prescription must be approved by the Investigator and the Medical Monitor.
18. Significant alcohol intake as measured by a phosphatidylethanol (PEth) level ≥ 200 ng/mL AND significant alcohol use, as determined by the Alcohol Use Disorders Identification Test (AUDIT-C) alcohol consumption questionnaire (Appendix 3).
19. Criterion deleted per Prot. v3.0.
20. Consumption of ≥ 21 units of alcohol per week in males and ≥ 14 units of alcohol per week in females for two years prior to screening, where a “unit” of alcohol is equivalent to a 12-ounce beer, 4-ounce glass of wine, or 1-ounce shot of hard liquor.
21. Use of any prohibited concomitant medications as described in Section 6.4 within 3 months prior to screening
a. Weight loss medications.
b. Any medication that is contraindicated according to the rosuvastatin package insert (Appendix 5) or if subject has a known hypersensitivity to rosuvastatin product components (Section 6.1.3).
c. Hepatotoxic medications (Appendix 6); allopurinol allowed.
d. Anabolic steroids.
22. History of statin intolerance, as defined by presence of significant side effects while on statins and/or inability to take or use statins for treatment.
23. Prior participation in a clinical trial of aldafermin unless previously enrolled into a placebo arm of the trial.
24. History of severe allergic or anaphylactic reactions to recombinant therapeutic proteins, fusion proteins, or chimeric, human, or humanized antibodies.
25. Participation in a study of another investigational agent within 28 days or five half-lives of the drug (whichever is longer) prior to Screening. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. The primary efficacy endpoint is the change in Enhanced Liver Fibrosis (ELF) score from baseline to Week 48 with aldafermin or matched placebo.
2. The primary safety endpoint is frequency, severity and timing of adverse events (AEs) and serious adverse events (SAEs). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
end point 1: after 48 weeks of treatment with aldafermin or matched placebo
end point 2: throughout the study |
|
| E.5.2 | Secondary end point(s) |
1. Improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis), after 48 weeks of treatment with aldafermin or matched placebo. , in subjects who had a minimum 1 point in each category (hepatocellular ballooning, steatosis, and lobular inflammation) of NAFLD Activity Score (NAS) at baseline as determined by central pathologist evaluation.
2. Improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis score) after 48 weeks of treatment with aldafermin or matched placebo.
3. Changes from baseline in fibrosis as measured by Collagen Proportional Area (CPA) and/or Second Harmonic Generation (SHG) methodologies at Week 48.
4. Aldafermin concentrations pre-dose at all treatment visits and 4-hours post-dose at Day 1, Week 24, and Week 48 in all subjects. In a subset of subjects participating in an optional PK study, full PK profiles up to 24 hours will be assessed at Day 1 and steady state at end of treatment (end of treatment, Week 48).
5. Changes from baseline over time in C4 and serum bile acids and compared to placebo.
6. Changes from baseline over time in Pro-C3 compared to placebo.
7. Changes from baseline over time in alanine transaminase (ALT) and aspartate transaminase (AST) and compared to placebo in subjects with elevated transaminases at baseline.
8. Changes from baseline over time in liver stiffness measure (LSM by FibroScan®) and compared to placebo. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. pre-dose at all treatment visits and 4-hours post-dose at Day 1, Week 24, and Week 48 in all subjects
2. at week 48
3. End of treatment period
4. at week 48 |
|
| 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 |
|
| 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 | 4 |
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| 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 |
| Australia |
| Hong Kong |
| United States |
| Belgium |
| France |
| Germany |
| Poland |
| United Kingdom |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| Last Subject Last Visit (LSLV). If the subject’s LDL-C value is at or near baseline at the Week 54 visit, the subject will end their participation in the trial and the EOS will be Week 54;However, if the subject does not meet this criterion, a follow up visit at Week 58 to further assess the LDL-C level will be required and the subject’s EOS visit will be at Week 58. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| 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 | 0 |
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