Non-alcoholic Steatohepatitis in patients with two additional features of metabolic syndrome -overweight or obesity and Diabetes Mellitus type II or pre-diabetes. MedDRA version: 20.0 Level: PT Classification code 10053219 Term: Non-alcoholic steatohepatitis System Organ Class: 10019805 - Hepatobiliary disorders
Conditions
Interventions
Product Name: Aramchol
Product Code: Aramchol
Pharmaceutical Form: Tablet
INN or Proposed INN: Aramchol
CAS Number: 246529-22-6
Sponsors
GALMED Pharmaceuticals LTD.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female age 18 to 75 years. 2. BMI between 25kg/m2 to 40kg/m2 or waist circumference between 88cm to 200cm for women, and between 102cm to 200cm for men. If there is deviation above the upper limit, please consult the MRI center, to ensure that the machine is suitable for the patient 3. Known type II Diabetes Mellitus or pre-Diabetes according to American Diabetes Association. One of the following 3 criteria is needed for pre-Diabetes: Fasting Plasma Glucose > 100mg/dl (5.5mmol/l) or 2hPG following 75g OGTT > 140 (7.8 mmol/l) mg/dl or HbA1c > 5.7%. HbA1c can be repeated at Investigator’s discretion 4. Histologically proven Steatohepatitis on a diagnostic liver biopsy performed either during Screening , or within 6 months before screening visit, confirmed by central laboratory reading of the slides (steatosis =1 + inflammation =1 + ballooning =1). Total activity NAS score of 4 or more. 5. Liver fat concentration of 5.5% or more as measured by NMRS. 6. Biopsies with an activity NAS score of 4 or more. 7. Normal synthetic liver function (serum albumin >3.2g/dl, INR 0.8-1.2, conjugated bilirubin 400IU/day), Polyunsaturated fatty acid (>2g/day), Ursodeoxycholic acid or fish oil can be included if drugs are stopped at least 3 months prior to diagnostic liver biopsy (and are not started during the trial). These treatments-dosages are allowed if they were stable for at least 12 months prior to biopsy and can remain stable throughout the study. (Dosages less than the amounts stated above are allowed without washout- or stable-period restrictions). 13. For patients with type II Diabetes, glycaemia must be controlled (Glycosylated Hemoglobin A1c = 9% while any HbA1c change should not exceed 1.5% during the 6 months prior to enrollment). Treatments with anti-diabetic medications (except for those mentioned in Exclusion 16) are permitted if glycaemia is self-monitored by the patient. HbA1c can be repeated at Investigator’s discretion. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 200 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 40
Exclusion criteria
Exclusion criteria: 1. Patients with other active (acute or chronic) liver disease other than NASH (e.g. viral hepatitis, unless eradicated at least 3 years prior to screening; genetic hemochromatosis; Wilson disease; alpha 1antitripsin deficiency; alcohol liver disease, drug induced liver disease) at the time of randomization. 2. Patients with clinically or histologically documented liver cirrhosis (CRN fibrosis score =4). 3. Known alcohol and/or any other drug abuse or dependence in the last five years. 4. Known history or presence of clinically significant cardiovascular, hepatic other than NASH, gastrointestinal, metabolic other than Diabetes Mellitus, neurologic, pulmonary, endocrine, psychiatric,neoplastic disorder or nephrotic syndrome, that in the opinion of the Investigator warrant exclusion from the study. 5. Patients with familial (i.e., genetic) hypertriglyceridemia and familial (i.e., genetic) hypercholesterolemia. 6. History or presence of any disease or condition known to interfere with the absorption, distribution, metabolism or excretion of drugs including bile salt metabolism (e.g. inflammatory bowel disease (IBD); previous intestinal (ileal or colonic) operation; chronic pancreatic; celiac disease or previous vagotomy. Ongoing chronic constipation. 7. Patients with heart or brain pacemaker. (i.e., implantable neurological devices). 8. Surgery within three months of screening which involved stent implantation of metal devices (e.g., knee, hip etc.) 9. Weight loss of more than 5% within 6 months prior to randomization. 10. History of bariatric surgery within 5 years of liver biopsy. 11. Uncontrolled arterial hypertension. 12. Women who are pregnant or breast feeding. 13. Diabetes Mellitus other than type II (type I, endocrinopathy, genetic syndromes etc.). 14. Patients with HIV infection. 15. Daily alcohol intake >20 g/day for women and >30 g/day for men (on average per day), as per medical history. 16. Treatment with other anti-diabetic medications: GLP-1 receptor agonists and Thiazolidinediones (TZDs) unless started at least 12 months prior to biopsy and on stable dose over 6 months. In case GLP-1 receptor agonist being stopped, it should be at least 6 months prior to biopsy, as per medical history. 17. SGLT-2 Inhibitors, Metformin, fibrates, statins, insulin, DPP-4 inhibitors and sulfonylurea unless the prescribed dose has been stable for the last 6 months prior to the biopsy. 18. Treatment with Valproic acid, Tamoxifen, Methotraxete, Amiodarone or chronic treatment with anti-cholinergic agents, corticosteroids, high dose estrogen and tetracycline within 12 months prior to the screening visit. 19. Chronic antibiotic treatment (e.g. Rifaximin). 20. Homeopathic and/or alternative treatments. Any treatment should be stopped during the screening period, at least 48 hours before randomization. 21. Uncontrolled hypothyroidism defined as Thyroid Stimulating Hormone >2X the upper limit of normal (ULN). Thyroid dysfunction controlled for at least 6 months prior to screening is permitted. 22. Patients with renal dysfunction eGFR< 40. 23. Unexplained serum creatine phosphokinase (CPK)
Design outcomes
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Proportion (%) of subjects with CRN fibrosis score improvement 2. Proportion (%) of subjects with NAS score improvement without worsening of CRN fibrosis score. 3. Proportion (%) of subjects with SAF activity score improvement without worsening of CRN Fibrosis Score. 4. Proportion (%) of subjects with NASH resolution without worsening of CRN fibrosis score 5. Change from baseline to Week 52/Termination in ALT (U/L) levels. Exploratory endpoints: 1. Change from baseline to Week 52/Termination in HOMA-IR (UNITS). 2. Change from baseline to Week 52/Termination in HEMOGLOBIN A1C (%). 3. Change from baseline to Week 52/Termination in ADIOPONECITINE (TOTAL) (mg/L). 4. Change from baseline to Week 52/Termination in LEPATIN (pg/mL) / ADIOPONECITINE (TOTAL) (mg/L) ratio (LAR) 5. Change from baseline to Week 52/Termination in inflammation and fibrosis biomarkers: FIBRINOGEN (ACT) (g/L), CYTOKERATIN 18 (M-30) (U/L), CYTOKERATIN 18 (M-65) (U/L), hs-CRP (mg/L), HS-IL6 (ng/L), TNFa [HS-TNF A (ng/L)] and NAFLD fibrosis score (NFS). 6. Change from baseline to Week 52/Termination in body weight and in waist circumference. 7. Change from baseline to Week 52/Termination in fatty liver index (FLI). 8. Endothelial function. 9. Aramchol blood trough level. 10. Metabolomics. 11. Genetic profiling. ; Timepoint(s) of evaluation of this end point: 1. At screening and at week 52. 2. At screening and at week 52. 3.At screening, baseline, visit 2, visit 7, visit 10, visit 11. 4. At screening, week 24, week 52, and unscheduled visit. 5. At screening, week 8, week 24, week 40, week 52, and unscheduled visit. | — |
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the efficacy on steatosis reduction as measured by NMRS of two Aramchol doses (400 mg and 600 mg), once daily for 52 weeks vs placebo. ; Secondary Objective: 1. To evaluate the efficacy of Aramchol on CRN Fibrosis Score by liver biopsy. 2. To evaluate the efficacy of Aramchol on disease activity as measured by NAS and SAF activity score 3. To evaluate the efficacy of Aramchol on NASH resolution by liver biopsy. 4. To evaluate the effect of Aramchol on ALT levels. Exploratory objectives: 1. To evaluate the effect of Aramchol on metabolic parameters. 2. To compare two doses in order to choose the optimal dose for pivotal Phase III studies. 3. To assess Aramchol’s effect on NASH activity by non-invasive diagnostic methods. 4. To validate new non-invasive tests for the diagnostic and assessments of Aramchol’s effect. 5. To conduct blood trough level of Aramchol. ;Primary end point(s): Percent (%) change from baseline to end of study in liver triglycerides ratio as measured by NMRS.;Timepoint(s) of evaluation of this end point: At screening and at week 52 | — |
Countries
Chile, France, Germany, Israel, Italy, Lithuania, Mexico, Peru, Romania, United States
Contacts
Public ContactEphry Gilad
GALMED Pharmaceuticals LTD.
Outcome results
None listed