Efficacy and Safety of Guanabenz for Nonalcoholic Fatty Liver Disease

Phase II Physician-initiated Clinical Trial Investigating the Efficacy and Safety of Guanabenz Acetate for Non-alcoholic Fatty Liver Disease Associated With Hypertension

To investigate the efficacy and safety of 4 mg/day of WY-8678 (guanabenz acetate) and 8 mg/day of WY-8678 (guanabenz acetate) in patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH patients) with hypertension

Study Overview

• Status: Active, not recruiting
• Conditions: Nonalcoholic Steatohepatitis; Nonalcoholic Fatty Liver
• Intervention / Treatment: Drug: Experimental: 4 mg/day of WY-8678 (guanabenz acetate); Drug: Experimental: 8 mg/day of WY-8678 (guanabenz acetate)

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Kanagawa
    • Yokohama, Kanagawa, Japan, 236-0004
      • Yokohama City University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients who have received a full explanation about this study and who have provided written consent.
2. Patients ≥ 20 years of age ≤ 75 years of age at the time consent was provided.
3. Patients diagnosed with essential hypertension and whose systolic blood pressure at the time of screening is ≥ 130 mmHg and/or diastolic blood pressure is ≥ 85 mmHg (according to the diagnostic criteria for metabolic syndrome)

4. Patients diagnosed with NAFLD/NASH who meet the following criteria (1) or (2) (1) Patients diagnosed with NAFLD who meet the following three criteria: ・Diagnostic imaging or histological evidence of fatty liver, ・Alcohol intake < 30 g/day for men and < 20 g/day for women for 12 or more consecutive weeks one year before screening, ・Absence of other factors that cause fattening or chronic liver disease. (2) Patients with a definitive diagnosis of NASH by biopsy within 32 weeks before screening * The definitive diagnostic criteria for NASH are defined as a fibrosis stage in liver biopsy in the evaluation using the "NASH Clinical Research Network (CRN) criteria" by an F1-F3 pathologist and a NAFLD activity score (NAS) ≥4 points (each item has one or more points): ・Steatosis (0-3 points)

   • Ballooning (0-2 points)
   • Inflammation in the lobules (0-3 points)
5. Patients with magnetic resonance imaging (MRI)-proton density fat fraction (PDFF) liver fat mass ≥ 8% at screening.
6. Patients with magnetic resonance elastography (MRE) value ≤ 3.6 kPa at screening.
7. Patients with a body mass index (BMI) ≥ 25 kg/m2 at the time of screening.
8. Patients receiving diet or exercise therapy 12 weeks before screening, with no improvement.
9. Patients who are willing to maintain a stable diet and physical activity during the clinical trial.

Exclusion Criteria:

1. Pregnant, lactating, potentially pregnant women, or patients who do not agree to contraception during the trial period.
2. Patients who have taken guanabenz acetate within 16 weeks prior to screening or who have participated in other clinical studies (observational studies are excluded).

3. Patients with drug allergies to guanabenz acetate. 4. Patients with liver failure or cirrhosis. 5. Patients with the following laboratory test values:

(1) Alanine aminotransferase (ALT) > 430 IU/L (males) or > 240 IU/L (female); or aspartate aminotransferase (AST) > 300 IU/L (males and females) (2) Prothrombin time-international normalized ratio (PT-INR) ≥ 1.5 (excluding anticoagulant therapy) (3) Total bilirubin value > 2.0 mg/dL (excluding definitive diagnosis of Gilbert syndrome) (4) Platelet count < 80,000/μL (5) Estimated glomerular filtration ratio (eGFR) < 45 (calculated by body surface area correction: standardized eGFR) 6. Patients with a history of acute or chronic liver disease other than NAFLD/NASH and complications:

1. Patients suffering from hepatitis B (defined by hepatitis B surface (HBs) antigen positive at the time of screening) or hepatitis C (defined by hepatitis C virus (HCV) antibody positive at the time of screening). However, anti-HCV antibody positive patients who are judged to be negative for hepatitis C virus ribonucleic acid (HCV-RNA) can be registered if they can be confirmed to be negative for at least one year before screening.
2. Patients with autoimmune hepatitis.
3. Patients with primary biliary cholangitis, primary sclerosing cholangitis, Wilson's disease, α1-antitrypsin deficiency, hemochromatosis or iron overload, drug-induced or alcoholic liver disease, or a history of known biliary atresia.
4. Patients with suspicion or definitive diagnosis of hepatocellular carcinoma. 7. Patients with a history of human immunodeficiency virus (HIV) infection. 8. Patients with findings of portal hypertension (complications: ascites, hepatic encephalopathy, varicose veins, splenomegaly).

9. Patients with a history of NAFLD-related drugs (amiodarone, methotrexate, systemic glucocorticoids, tetracycline, tamoxifen, higher doses of estrogen, anabolic steroids or valproic acid than used for hormone replacement) or other hepatotoxins for at least 4 weeks prior to screening.

10. Patients who have used the following drugs:

1. Patients who used insulin, glucagon-like peptide-1 (GLP-1) receptor agonists, SGLT2 inhibitors, or thiazolidine 12 weeks before screening,
2. Patients who used ursodeoxycholic acid or vitamin E 12 weeks before screening,
3. Patients whose doses of dyslipidemia drugs or antihypertensive drugs were changed 12 weeks before screening,
4. Patients whose dose of oral diabetes treatment drug (dipeptidyl peptidase 4 [DPP-4] inhibitor, sulfonylurea [SU] preparation, α-glucosidase inhibitor, metformin) was changed 12 weeks before screening,
5. Patients who used drugs known to have a significant effect on body weight (including over-the-counter drugs for weight loss) 12 weeks before screening,
6. Patients using central nervous system depressants (barbital, sodium thiopental, morphine hydrochloride hydrate, brotizolam, diazepam, etc.).

11. Patients with 10% weight change 24 weeks before screening. 12. Patients scheduled to undergo surgery after obesity surgery (such as gastroplasty and Roux-en-Y gastric bypass surgery) or during the trial period.

13. Patients with a history of type 1 diabetes. 14. Patients with hemoglobin A1c (HbA1c) > 9.5% at screening or with uncontrolled type 2 diabetes.

15. Patients with hyperthyroidism or hypothyroidism, or screening results showing thyroid dysfunction. However, for hypothyroidism, registration is possible if thyroid replacement therapy is received 12 weeks before screening and the test values are stable.

16. Patients with a history of New York heart association functional classification (NYHA classification) class III or IV heart failure due to factors other than hypertension.

17. Patients with a history of myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, or stroke or major surgery 24 weeks before screening.

18. Patients with a history of substance abuse. 19. Patients with malignant tumors. However, patients who have undergone radical surgery, patients who have completed chemotherapy/radiation therapy, and patients who are undergoing hormone therapy can be registered.

20. Patients with known intolerance to MRI or patients who are contraindicated for MRI examination.

21. Other patients who the principal investigator or sub-investigator deems inappropriate for conducting this clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 4 mg/day of WY-8678 (guanabenz acetate)	Drug: Experimental: 4 mg/day of WY-8678 (guanabenz acetate); Patients with nonalcoholic fatty liver disease are administered 4 mg/day of WY-8678 (guanabenz acetate) twice daily for 16 weeks
Experimental: 8 mg/day of WY-8678 (guanabenz acetate)	Drug: Experimental: 8 mg/day of WY-8678 (guanabenz acetate); Patients with nonalcoholic fatty liver disease are administered 8 mg/day of WY-8678 (guanabenz acetate) twice daily for 16 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of those where the liver fat content (%) measured by MRI-PDFF at 16 weeks decreased by ≥ 3.46% from baseline (%)	MRI-PDFF	Week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of those where the liver fat content (%) measured by MRI-PDFF at 16 weeks decreased by 3.46% or more from baseline for 4 mg group and 8 mg group (%)	MRI-PDFF	Week 16
The absolute change in liver fat content measured by MRI-PDFF	MRI-PDFF	Week 16
Rate of change in ALT	Serum	Week 16
Rate of change in AST	Serum	Week 16
Rate of change in gamma-glutamyl transferase (γ-GTP)	Serum	Week 16
Rate of change in weight	Body weight	Week 16
Rate of change in blood lipids	Serum. Blood lipids defined as (chylomicron cholesterol, chylomicron triglyceride, lipoprotein cholesterol, low-density lipoprotein [LDL] triglyceride, very low-density lipoprotein [VLDL] cholesterol, VLDL triglyceride, free cholesterol, apoprotein A1, apoprotein B, adipsin, free fatty acid).	Week 16
Rate of change in insulin resistance (HOMA-IR)	Blood	Week 16
Rate of change in liver stiffness	MR elastography	Week 16
Rate of change in fibrosis markers (enhanced liver fibrosis [ELF] score)	Serum	Week 16
Rate of change in fibrosis markers (enhanced liver fibrosis Fibrosis-4 [FIB-4])	Serum	Week 16
Occurrence rate of adverse events	Safety	Week 0-16

Collaborators and Investigators

• Sponsor: Yokohama City University

Publications and helpful links

General Publications

• Iwaki M, Kessoku T, Tanaka K, Ozaki A, Kasai Y, Yamamoto A, Takahashi K, Kobayashi T, Nogami A, Honda Y, Ogawa Y, Imajo K, Yoneda M, Kobayashi N, Saito S, Nakajima A. Efficacy and safety of guanabenz acetate treatment for non-alcoholic fatty liver disease: a study protocol for a randomised investigator-initiated phase IIa study. BMJ Open. 2022 Jul 12;12(7):e060335. doi: 10.1136/bmjopen-2021-060335.

Study record dates

Study Major Dates

• Study Start (Actual): October 29, 2021
• Primary Completion (Anticipated): February 28, 2023
• Study Completion (Anticipated): June 30, 2023

Study Registration Dates

• First Submitted: September 24, 2021
• First Submitted That Met QC Criteria: October 15, 2021
• First Posted (Actual): October 19, 2021

Study Record Updates

• Last Update Posted (Actual): September 27, 2022
• Last Update Submitted That Met QC Criteria: September 25, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Nonalcoholic Steatohepatitis; Nonalcoholic Fatty Liver; Guanabenz; Phase 2 trial
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Guanabenz
• Other Study ID Numbers: YCU-21001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No