Namodenoson in the Treatment of Non-Alcoholic Steatohepatitis (NASH)

Phase 2

Recruiting

• Conditions: NASH - Nonalcoholic Steatohepatitis
• Interventions: Drug: Namodenoson; Drug: Placebo

• Registration Number: NCT04697810
• Lead Sponsor: Can-Fite BioPharma

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.

Study Timeline

• Study First Submitted: 2021-01-04
• Study First Submitted QC: 2021-01-05
• Study First Posted: 2021-01-06
• Study Start: 2021-12-10
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-30
• Last Update Posted: 2024-07-31
• Primary Completion: 2025-04-15
• Study Completion: 2025-10-15

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 114

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Namodenoson	Namodenoson	Namodenoson capsules orally 25 mg every 12 hours for 36 weeks
Placebo	Placebo	Matching placebo capsules orally 25 mg every 12 hours for 36 weeks

Primary Outcome Measures

Name	Time	Method
Adverse events (AEs)	36 weeks	Incidence of AEs
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)

Secondary Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (24)

911 IMSP Spitalul Clinic Republican "Timofei Mosneaga"; 🇲🇩 Chisinau, Moldova, Republic of

933 Clinic of Gastroenterology, University Multiprofile Hosptial for Active Treatment; 🇧🇬 Sofia, Bulgaria

Hadassah Medical Center; 🇮🇱 Jerusalem, Israel

936 Office of Gastroenterology, Diagnostic - Consultative Center XX; 🇧🇬 Sofia, Bulgaria

924 CHC "dr Dragisa Misovic" - Dedinje Belgrade; 🇷🇸 Belgrade, Serbia

934 Second Dept of Internal Disease, MHAT Sveta Karidad EAD; 🇧🇬 Plovdiv, Bulgaria

517 Saroka University Medical Center; 🇮🇱 Be'er Sheva, Israel

937 Office of Gastroenterology, Diagnostic - Consultative Center Alexandrovska; 🇧🇬 Sofia, Bulgaria

906 Spitalul Sfanta Maria; 🇷🇴 Bucharest, Romania

904 SUUMC Carol Davilla, Department Diabet; 🇷🇴 Bucharest, Romania

901 Medical Center Dr. Ianosi; 🇷🇴 Craiova, Romania

922 UCC Zvezdara Belgrade; 🇷🇸 Belgrade, Serbia

921 UCC Nis; 🇷🇸 Niš, Serbia

932 Office of Gastroenterology, Medical Center Sansi EOOD; 🇧🇬 Ruse, Bulgaria

931 Clinic of Gastroenterology, Acibadem City Clinic Multiprofile Hospital for Active Treatment Tokuda EAD, Sofia; 🇧🇬 Sofia, Bulgaria

935 Dept of Gastroent., Univ Multiprofile Hospital for Active Treatment and Emergency Medicine; 🇧🇬 Sofia, Bulgaria

938 Clinic of Gastroenterology, University Multiprofile Hospital for Active Treatment "Sv. Ivan Rilski"; 🇧🇬 Sofia, Bulgaria

902 Cluj County Clinical Emergency Hospital, 3rd Dept of Internal Medicine; 🇷🇴 Cluj-Napoca, Romania

941 Univ of Clinical Centre of the Republic of Srpska; 🇧🇦 Banja Luka, Bosnia and Herzegovina

942 Health Inst General Hospital, Dept of Internal Medicine; 🇧🇦 Prijedor, Bosnia and Herzegovina

912 SP Spitalul Ministerului Sanatatii, Muncii si Protectiei Sociale; 🇲🇩 Chisinau, Moldova, Republic of

903 Central Pentru Studiul Metabolismului; 🇷🇴 Bucharest, Romania

905 County Hospital Timisoara; 🇷🇴 Timişoara, Romania

923 Military Medical Academy Belgrade; 🇷🇸 Belgrade, Serbia