NASH - Nonalcoholic Steatohepatitis
Conditions
Brief summary
Subjects with biopsy-proven NASH will be randomly assigned in a 2:1 ratio to oral doses of namodenoson 25 mg every 12 hours or matching placebo every 12 hours for 36 weeks. Subjects will be evaluated regularly for safety, and efficacy biomarkers will be measured at Baseline and Weeks 6, 12, 24, and 36. At Week 36, all subjects will undergo liver biopsy.
Detailed description
This is a multicenter, randomized, double-blind, placebo-controlled study in subjects with a diagnosis of NASH and F1-3 fibrosis. Subjects will undergo Screening procedures during the 6 weeks preceding Baseline. Subjects (n = \ 114) will be randomly assigned in a 2:1 ratio to oral doses of namodenoson 25 mg every 12 hours or matching placebo every 12 hours for 36 weeks. Subjects will be evaluated regularly for safety, and efficacy biomarkers will be measured at Baseline and Weeks 6, 12, 24, and 36. At Week 36, all subjects will undergo post-treatment liver biopsy, which will be interpreted by a blinded expert hepatopathologist. Subjects will return for a follow-up visit 6 weeks after completion of the last dose of study drug.
Interventions
DRUGNamodenoson
25 mg q12hours x 36 weeks
DRUGPlacebo
Matching capsules q12hours x 36 weeks
Sponsors
Can-Fite BioPharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Placebo capsules are identical in appearance to namodenoson capsules.
Intervention model description
Subjects will be randomly assigned in a 2:1 ratio of namodenoson 25 mg or matching placebo, according to a computer-generated randomization schedule. Blocked randomization will be programmed using a pre-specified block size. Double-blinding will be maintained throughout the trial.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 and the slides are available for central read prior to randomization, this biopsy can be waived. 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: * Obesity, defined waist circumference \>88 cm for women or \>102 cm for men * Hypertriglyceridemia, defined as \>150 mg/dL (\>1.7 mmol/L) or on drug treatment for hypertriglyceridemia * Reduced high-density lipoprotein (HDL) cholesterol, defined as \<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 ≤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 at least 1.0 x 109/L * Platelet count at least 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, permanently sterile or are post-menopausal, defined as no menses for at least 1 year without an alternative medical cause and 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.
Exclusion criteria
1. 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. 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. 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. 11. Active rheumatoid arthritis treated with small-molecule (including methotrexate) or biologic disease-modifying anti-rheumatic agent concurrently or within 1 year. 12. Use of any immunosuppressive medication, anti-inflammatory monoclonal antibody treatment, or chronic systemic corticosteroids \>10 mg prednisone-equivalent concurrently or within 1 year. 13. More than 7 days of treatment with valproic acid, tamoxifen, amiodarone, or anti-cholinergic agents within 3 months. 14. Uncontrolled or clinically unstable thyroid disease. 15. 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. 16. Angina, myocardial infarction, cerebrovascular accident, coronary/peripheral artery bypass graft surgery, transient ischemic attack, or pulmonary embolism within 3 months. 17. QTcF interval on Screening Visit ECG or an average of triplicate Baseline Visit ECGs \> 450 milliseconds (msec) for males or \> 470 msec for females. 18. A condition which increases proarrhythmic risk, including hypokalemia, hypomagnesemia, or congenital Long QT Syndrome. 19. Ongoing or planned use of a concomitant medication that is on the CredibleMedsTM list of drugs known to cause Torsades des Pointes. 20. Active gastrointestinal disease which could interfere with the absorption of oral medication. 21. Any severe, acute, or chronic medical or psychiatric condition, or laboratory abnormality that would make the patient inappropriate for entry into this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Non-Alcoholic Fatty Liver Disease (NAFLD) activity score (NAS) | 36 weeks | 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) |
| Adverse events (AEs) | 36 weeks | Incidence of AEs |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Alanine transaminase (ALT) mean | 36 weeks | Mean percent change from Baseline in serum ALT level |
| Steady-state blood level of namodenoson | 36 weeks | Plasma trough concentration (ng/mL) of namodenoson taken at pre-dose samples |
Other
| Measure | Time frame | Description |
|---|---|---|
| Released N-terminal pro-peptide of type III collagen neoepitope (Pro-C3) | 36 weeks | Change from Baseline in Pro-C3 |
| Serum Enhanced Liver Fibrosis (ELF) Score | 36 weeks | Change from Baseline in ELF Score, which is a continuous scale starting at zero, with higher scores indicating more severe disease |
| FibroScan controlled attenuation parameter (CAP) | 36 weeks | Change from Baseline in CAP |
| FibroScan-AST (FAST) Score | 36 weeks | Change from Baseline in FAST Score, which is a decimal score from 0 to 1, with higher scores indicating more severe disease |
| ALT absolute | 36 weeks | Absolute change from Baseline in serum ALT |
| Gamma-glutamyl transferase (GGT) | 36 weeks | Change from Baseline in serum GGT |
| Fibrosis-4 (Fib-4) Index | 36 weeks | Change from Baseline in Fib-4 Index |
| NASH resolution | 36 weeks | Proportion of subjects who achieve histologic NASH resolution as defined by a ballooning score of 0 and an inflammation score of 0-1 without worsening of fibrosis |
| NASH fibrosis improvement | 36 weeks | Proportion of subjects who achieve histologic NASH improvement by at least 1 point without worsening of NASH |
| Aspartate transaminase (AST) | 36 weeks | Change from Baseline in serum AST |
| ALT threshold | 36 weeks | Proportion of subjects who achieve ≥17-point reduction from Baseline in serum ALT |
| Weight | 36 weeks | Change from Baseline in body weight |
| Adiponectin | 36 weeks | Change from Baseline in serum adiponectin level |
Countries
Bosnia and Herzegovina, Bulgaria, Israel, Moldova, Romania, Serbia
Contacts
Primary ContactZivit Harpaz
Backup ContactPnina Fishman, PhD
Outcome results
None listed