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

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ClinicalTrials.gov Identifier: NCT04697810
Recruitment Status : Recruiting
First Posted : January 6, 2021
Last Update Posted : June 18, 2023
Sponsor:
Information provided by (Responsible Party):
Can-Fite BioPharma

Study Description
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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.

Condition or disease Intervention/treatment Phase
NASH - Nonalcoholic Steatohepatitis Drug: Namodenoson Drug: Placebo Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 114 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Placebo capsules are identical in appearance to namodenoson capsules.
Primary Purpose: Treatment
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)
Actual Study Start Date : December 10, 2021
Estimated Primary Completion Date : April 15, 2025
Estimated Study Completion Date : October 15, 2025

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Namodenoson
Namodenoson capsules orally 25 mg every 12 hours for 36 weeks
 Drug: Namodenoson
25 mg q12hours x 36 weeks
Other Name: CF102
Placebo Comparator: Placebo
Matching placebo capsules orally 25 mg every 12 hours for 36 weeks
 Drug: Placebo
Matching capsules q12hours x 36 weeks
Other Name: Inactive control


Outcome Measures
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Primary Outcome Measures :
  1. Non-Alcoholic Fatty Liver Disease (NAFLD) activity score (NAS) [ Time Frame: 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)

  2. Adverse events (AEs) [ Time Frame: 36 weeks ]
    Incidence of AEs


Secondary Outcome Measures :
  1. Alanine transaminase (ALT) mean [ Time Frame: 36 weeks ]
    Mean percent change from Baseline in serum ALT level

  2. Steady-state blood level of namodenoson [ Time Frame: 36 weeks ]
    Plasma trough concentration (ng/mL) of namodenoson taken at pre-dose samples


Other Outcome Measures:
  1. ALT absolute [ Time Frame: 36 weeks ]
    Absolute change from Baseline in serum ALT

  2. ALT threshold [ Time Frame: 36 weeks ]
    Proportion of subjects who achieve ≥17-point reduction from Baseline in serum ALT

  3. Weight [ Time Frame: 36 weeks ]
    Change from Baseline in body weight

  4. Adiponectin [ Time Frame: 36 weeks ]
    Change from Baseline in serum adiponectin level

  5. Released N-terminal pro-peptide of type III collagen neoepitope (Pro-C3) [ Time Frame: 36 weeks ]
    Change from Baseline in Pro-C3

  6. Serum Enhanced Liver Fibrosis (ELF) Score [ Time Frame: 36 weeks ]
    Change from Baseline in ELF Score, which is a continuous scale starting at zero, with higher scores indicating more severe disease

  7. FibroScan controlled attenuation parameter (CAP) [ Time Frame: 36 weeks ]
    Change from Baseline in CAP

  8. FibroScan-AST (FAST) Score [ Time Frame: 36 weeks ]
    Change from Baseline in FAST Score, which is a decimal score from 0 to 1, with higher scores indicating more severe disease

  9. Aspartate transaminase (AST) [ Time Frame: 36 weeks ]
    Change from Baseline in serum AST

  10. Gamma-glutamyl transferase (GGT) [ Time Frame: 36 weeks ]
    Change from Baseline in serum GGT

  11. Fibrosis-4 (Fib-4) Index [ Time Frame: 36 weeks ]
    Change from Baseline in Fib-4 Index

  12. NASH resolution [ Time Frame: 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

  13. NASH fibrosis improvement [ Time Frame: 36 weeks ]
    Proportion of subjects who achieve histologic NASH improvement by at least 1 point without worsening of NASH


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04697810


Contacts
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Contact: Zivit Harpaz +972-3-9241114 Zivit@canfite.co.il
Contact: Pnina Fishman, PhD +972-3-9241114 pnina@canfite.co.il

Locations
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Sponsors and Collaborators
Can-Fite BioPharma
Investigators
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Study Director: Michael H Silverman, MD BioStrategics Consulting Ltd
More Information
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Publications:

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Responsible Party: Can-Fite BioPharma
ClinicalTrials.gov Identifier: NCT04697810    
Other Study ID Numbers: CF102-212LD
First Posted: January 6, 2021    Key Record Dates
Last Update Posted: June 18, 2023
Last Verified: June 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Fatty Liver
Non-alcoholic Fatty Liver Disease
Liver Diseases
Digestive System Diseases