| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Non-Alcoholic Steatohepatitis (NASH) and F1-3 fibrosis. | |
| E.1.1.1 | Medical condition in easily understood language | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | • Evaluate the efficacy of namodenoson as compared to placebo in subjects with NASH, as determined by the proportion of subjects who achieve a ≥2-point improvement in the non-alcoholic fatty liver disease (NAFLD) activity score (NAS) of the Non-Alcoholic Steatohepatitis Clinical Research Network (NASH CRN) (Kleiner 2005); and
• Characterize the safety profile of namodenoson in subjects with NASH. | |
| E.2.2 | Secondary objectives of the trial | • Evaluate the efficacy of orally administered namodenoson in subjects with NASH, as determined by the mean Percent Change From Baseline (PCFB) in serum alanine aminotransferase (ALT) levels at Week 36; and
• Assess the pharmacokinetics (PK) of namodenoson in this population. | |
| 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 | | PK of Namodenoson will be assessed through sparse sampling. | |
| E.3 | Principal inclusion criteria | 1. At least 18 years of age.
2. AST at Screening of ≥20 IU/L.
3. FibroScan LSM ≥8.5 kPa.
4. Diagnosis of NASH by biopsy at Screening showing NAS ≥4 by central read, with a score of at least 1 point in each of the 3 histologic categories of steatosis, inflammation, and hepatocellular ballooning (Kleiner 2005). If the subject has had a qualifying liver biopsy within 6 months prior to Baseline, this biopsy can be waived as long as the slides are available for the central read prior to randomization (Section 12.4.9).
5. Concomitant biopsy-proven Stage 1-3 hepatic fibrosis by NASH CRN criteria by central read (Kleiner 2005).
6. At least 2 of the following criteria for the metabolic syndrome (Grundy 2005):
• Obesity, defined as waist circumference >88 cm for women or >102 cm for men
• Hypertriglyceridemia, defined as triglycerides >150 mg/dL (>1.7 mmol/L) or on drug treatment for hypertriglyceridemia
• Reduced high-density lipoprotein (HDL) cholesterol, defined as HDL cholesterol <40 mg/dL (<1.03 mmol/L) in men or <50 mg/dL (<1.3 mmol/L) in women
• History of hypertension, currently controlled in the judgment of the Investigator
• Elevated fasting glucose, defined as ≥100 mg/dL (≥5.6 mmol/L).
7. Acceptable hepatic metabolic and synthetic function, as indicated at Screening by:
• Serum albumin ≥3.5 gm/dL
• International normalized ratio (INR) ≤1.3
• Serum total bilirubin ≤2.0 mg/dL (unless subject has known Gilbert’s Syndrome).
8. The following laboratory values must be documented at Screening:
• Absolute neutrophil count ≥1.0 x 109/L
• Platelet count ≥150 x 109/L
• Estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73m2
9. Female subjects may be enrolled if they are not of childbearing potential, are permanently sterile or are post-menopausal, defined as no menses for at least 1 year without an alternative medical cause and follicle stimulating hormone (FSH) levels in the post-menopausal range.
10. Male subjects must refrain from sperm donation during treatment and until at least 90 days after the end of study drug dosing. Male subjects with fertile or pregnant partners must agree to use condoms throughout the course of the trial and for 3 months after.
11. Patients taking herbal supplements, homeopathic medications, or other alternative treatments must be on a stable regimen for at least 3 months prior to randomization.
12. Understand and provide written informed consent to participate.
13. Willing to undergo 2 liver biopsies.
14. Willing to comply with scheduled visits, treatment plans, laboratory assessments, and other study-related procedures. | |
| E.4 | Principal exclusion criteria | 1. Presence of ascites, hepatic encephalopathy, or other clinical evidence of cirrhosis.
2. Other active acute or chronic liver disease, such as autoimmune hepatitis, hepatitis B, hepatitis C, alcoholic liver disease, or hepatocellular carcinoma.
3. Seropositivity for markers of viral hepatitis or human immunodeficiency virus (HIV) at Screening. (Notes: If anti-hepatitis C virus (HCV) antibody is positive, a negative HCV ribonucleic acid (RNA) test is required for entry. Any prior treatment for HCV must have been completed at least 2 years prior to the qualifying liver biopsy.)
4. Weight loss of >5% within 3 months prior to Baseline.
5. History of bariatric surgery within 5 years of Screening.
6. Diabetes mellitus other than Type II.
7. Hemoglobin A1c >9.0% (subjects with diabetes).
8. Any contraindication to percutaneous liver biopsy.
9. Daily alcohol intake >20 g (2 units)/day for women and 30 g (3 units)/day for men (on average), as per Alcohol Use Disorders Identification Test (AUDIT) questionnaire at Screening or Baseline.
10. Treatment with therapeutic doses of Vitamin E (≥800-1000 IU daily), or any of the following anti-diabetic medications: GLP-1 receptor agonists (such as Januvia [sitagliptin], Byetta [incretin], etc.), pioglitazone, or SGLT2 inhibitors (“gliflozin” drugs); unless the dose and regimen has been stable for at least 3 months prior to Screening.
11. Active rheumatoid arthritis treated with small-molecule (including methotrexate) or biologic disease-modifying anti-rheumatic agent concurrently or within 1 year prior to Screening.
12. Use of any immunosuppressive medication, anti-inflammatory monoclonal antibody treatment, or chronic systemic corticosteroids >10 mg prednisone-equivalent concurrently or within 1 year prior to Screening.
13. More than 7 days of treatment with valproic acid, tamoxifen, amiodarone, or anti-cholinergic agents within 3 months prior to Screening.
14. Concomitant use of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) inhibitors and/or substrates with a narrow therapeutic index unless the medication can be taken at least 3 hours before or after taking the
investigational product (see Section 12.2).
15. Uncontrolled or clinically unstable thyroid disease, in the judgment of
the Principal Investigator.
16. Uncontrolled arterial hypertension or congestive heart failure (New York Heart Association Classification 3 or 4), or other heart disease which is, in the Investigator’s judgment, clinically unstable.
17. Angina, myocardial infarction, cerebrovascular accident, coronary/peripheral artery bypass graft surgery, transient ischemic attack, or pulmonary embolism within 3 months prior to initiation of study drug.
18. QTcF interval on Screening Visit ECG (average of triplicate) or an average of triplicate Baseline Visit ECGs > 450 milliseconds (msec) for males or > 470 msec for females (except when QT prolongation is associated with right or left bundle branch block, in which case enrollment is allowed).
19. A condition which increases proarrhythmic risk, including hypokalemia, hypomagnesemia, or congenital Long QT Syndrome.
20. Ongoing or planned use of a concomitant medication that is on the CredibleMedsTM list of drugs known to cause Torsades des Pointes (Appendix 1);
21. Active gastrointestinal disease which could interfere with the absorption of oral medication.
22. Any severe, acute, or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, may interfere with the informed consent process and/or with compliance with the requirements of the study, or may interfere with the interpretation of study results and, in the investigator’s opinion, would make the patient inappropriate for entry into this study. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | Primary Efficacy Endpoint
Primary efficacy Endpoint will be assessed through the proportion of subjects who achieve ≥2 point improvement in NASH histology on liver biopsy, using the NAS of the NASH CRN (Kleiner 2005).
Primary Safety Endpoints
Primary safety Endpoints will be assessed through the type, incidence, severity (graded by Common Terminology Criteria for Adverse Events (CTCAE) v5.0), timing,
seriousness, and relationship to treatment of AEs. | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | Week 36 or Early termination (after at least 24 weeks of dosing) | |
| E.5.2 | Secondary end point(s) | The key secondary efficacy endpoint is the PCFB to Week 36 of serum ALT levels, defined as:
PCFB = 100*[(Value at Week 36 – Value at Baseline) / Value at Baseline]. | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | |
| 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 | Yes |
| 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 | 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 | 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 | 2 |
| 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 | 12 |
| 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 | | Israel | | Bosnia and Herzegovina | | Moldova, Republic of | | Serbia | | Bulgaria | | Poland | | Romania | |
| 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 | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
