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

NASH - Nonalcoholic Steatohepatitis Clinical Trial

Official title:

A Phase 2B Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of Namodenoson in the Treatment of Non-Alcoholic Steatohepatitis (NASH)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04697810
• Other study ID #: CF102-212LD
• Status: Recruiting
• Phase: Phase 2
• Start date: December 10, 2021
• Est. completion date: October 15, 2025

Study information

• Verified date: June 2023
• Source: Can-Fite BioPharma
• Contact: Zivit Harpaz
• Phone: +972-3-9241114
• Email: Zivit[@]canfite.co.il
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 114
• Est. completion date: October 15, 2025
• Est. primary completion date: April 15, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Fatty Liver
• NASH - Nonalcoholic Steatohepatitis
• Non-alcoholic Fatty Liver Disease

Intervention

Drug:
• Namodenoson
25 mg q12hours x 36 weeks
• Placebo
Matching capsules q12hours x 36 weeks

Locations

Country	Name	City	State
Bosnia and Herzegovina	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
Bulgaria	934 Second Dept of Internal Disease, MHAT Sveta Karidad EAD	Plovdiv
Bulgaria	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	933 Clinic of Gastroenterology, University Multiprofile Hosptial for Active Treatment	Sofia
Bulgaria	935 Dept of Gastroent., Univ Multiprofile Hospital for Active Treatment and Emergency Medicine	Sofia
Bulgaria	936 Office of Gastroenterology, Diagnostic - Consultative Center XX	Sofia
Bulgaria	937 Office of Gastroenterology, Diagnostic - Consultative Center Alexandrovska	Sofia
Bulgaria	938 Clinic of Gastroenterology, University Multiprofile Hospital for Active Treatment "Sv. Ivan Rilski"	Sofia
Israel	517 Saroka University Medical Center	Be'er Sheva
Israel	Hadassah Medical Center	Jerusalem
Moldova, Republic of	911 IMSP Spitalul Clinic Republican "Timofei Mosneaga"	Chisinau
Moldova, Republic of	912 SP Spitalul Ministerului Sanatatii, Muncii si Protectiei Sociale	Chisinau
Romania	903 Central Pentru Studiul Metabolismului	Bucharest
Romania	904 SUUMC Carol Davilla, Department Diabet	Bucharest
Romania	906 Spitalul Sfanta Maria	Bucharest
Romania	902 Cluj County Clinical Emergency Hospital, 3rd Dept of Internal Medicine	Cluj-Napoca
Romania	901 Medical Center Dr. Ianosi	Craiova
Romania	905 County Hospital Timisoara	Timisoara
Serbia	922 UCC Zvezdara Belgrade	Belgrade
Serbia	923 Military Medical Academy Belgrade	Belgrade
Serbia	924 CHC "dr Dragisa Misovic" - Dedinje Belgrade	Belgrade
Serbia	921 UCC Nis	Niš

Sponsors (1)

Lead Sponsor	Collaborator
Can-Fite BioPharma

Countries where clinical trial is conducted

Bosnia and Herzegovina,  Bulgaria,  Israel,  Moldova, Republic of,  Romania,  Serbia, 

References & Publications (2)

Cohen S, Stemmer SM, Zozulya G, Ochaion A, Patoka R, Barer F, Bar-Yehuda S, Rath-Wolfson L, Jacobson KA, Fishman P. CF102 an A3 adenosine receptor agonist mediates anti-tumor and anti-inflammatory effects in the liver. J Cell Physiol. 2011 Sep;226(9):2438-47. doi: 10.1002/jcp.22593. — View Citation

Safadi R, Braun M, Francis A, Milgrom Y, Massarwa M, Hakimian D, Hazou W, Issachar A, Harpaz Z, Farbstein M, Itzhak I, Lev-Cohain N, Bareket-Samish A, Silverman MH, Fishman P. Randomised clinical trial: A phase 2 double-blind study of namodenoson in non-alcoholic fatty liver disease and steatohepatitis. Aliment Pharmacol Ther. 2021 Dec;54(11-12):1405-1415. doi: 10.1111/apt.16664. Epub 2021 Oct 20. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	ALT absolute	Absolute change from Baseline in serum ALT	36 weeks
Other	ALT threshold	Proportion of subjects who achieve =17-point reduction from Baseline in serum ALT	36 weeks
Other	Weight	Change from Baseline in body weight	36 weeks
Other	Adiponectin	Change from Baseline in serum adiponectin level	36 weeks
Other	Released N-terminal pro-peptide of type III collagen neoepitope (Pro-C3)	Change from Baseline in Pro-C3	36 weeks
Other	Serum Enhanced Liver Fibrosis (ELF) Score	Change from Baseline in ELF Score, which is a continuous scale starting at zero, with higher scores indicating more severe disease	36 weeks
Other	FibroScan controlled attenuation parameter (CAP)	Change from Baseline in CAP	36 weeks
Other	FibroScan-AST (FAST) Score	Change from Baseline in FAST Score, which is a decimal score from 0 to 1, with higher scores indicating more severe disease	36 weeks
Other	Aspartate transaminase (AST)	Change from Baseline in serum AST	36 weeks
Other	Gamma-glutamyl transferase (GGT)	Change from Baseline in serum GGT	36 weeks
Other	Fibrosis-4 (Fib-4) Index	Change from Baseline in Fib-4 Index	36 weeks
Other	NASH resolution	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	36 weeks
Other	NASH fibrosis improvement	Proportion of subjects who achieve histologic NASH improvement by at least 1 point without worsening of NASH	36 weeks
Primary	Non-Alcoholic Fatty Liver Disease (NAFLD) activity score (NAS)	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)	36 weeks
Primary	Adverse events (AEs)	Incidence of AEs	36 weeks
Secondary	Alanine transaminase (ALT) mean	Mean percent change from Baseline in serum ALT level	36 weeks
Secondary	Steady-state blood level of namodenoson	Plasma trough concentration (ng/mL) of namodenoson taken at pre-dose samples	36 weeks

External Links

•   Sponsor website