Liver Diseases Clinical Trial
— Aramchol_005Official title:
A Phase IIb, Double Blind Randomized, Controlled Clinical Trial, to Evaluate the Efficacy and Safety of Two Aramchol Doses Versus Placebo in Patients With Non-Alcoholic Steatohepatitis (NASH) - Aramchol 005 Study
Verified date | June 2021 |
Source | Galmed Pharmaceuticals Ltd |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
This is a multicenter, Phase IIb, randomized, double blind, placebo-controlled study designed to evaluate the efficacy and safety of two Aramchol doses in subjects that are 18 to 75 years of age, with Non-Alcoholic Steatohepatitis (NASH) confirmed by liver biopsy performed in a period of 6 months before entering the study, with overweight or obesity and who are pre diabetic or type II diabetic. Eligible subjects will be enrolled into three treatments arms: Aramchol 400 and 600 mg tablets and placebo tablets in ratio 2:2:1. The subjects will be evaluated at study sites for 11 scheduled visits during one year (52 weeks). After completion of the study treatment period, the subjects will be followed for an additional period of 13 weeks without study medication (until visit 11 (week 65)).
Status | Completed |
Enrollment | 247 |
Est. completion date | May 22, 2018 |
Est. primary completion date | May 22, 2018 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 75 Years |
Eligibility | Inclusion Criteria: 1. Male or female age 18 to 75 years. 2. BMI between 25kg/m2 to 40kg/m2 or waist circumference between 88 cm to 200 cm for women, and between 102 cm to 200 cm 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 (5.5 mmol/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 in the liver 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 < 35 µmol/L). 8. Understanding the nature of the study and signature of the written informed consent. 9. Negative pregnancy test at study entry for females of child bearing potential. 10. Females of child bearing potential practicing reliable contraception throughout the study period (including oral contraceptives) as well as negative pregnancy test at study entry. 11. Hypertensive patients must be well controlled by stable dose of anti-hypertensive medication for at least 2 months prior to screening. 12. Patients previously treated with vitamin E (>400IU/day), Polyunsaturated fatty acid (>2g/day) or Ursodeoxycholic acid or fish oil can be included if stopped or at least maintained on stable dose 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 6 months prior to enrolment). 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. 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 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, 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 metabolites (e.g. inflammatory bowel disease (IBD)), previous intestinal (ileal or colonic) operation, chronic pancreatitis, celiac disease or previous vagotomy. Ongoing Chronic constipation 7. Patients with heart or brain pacemaker (i.e., implantable neurological devices). 8. Surgery during the last three month before 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 and 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 for 6 months. In case of GLP-1 receptor agonists stopped, it should be at least 6 months before biopsy as per medical history. 17. SGLT-2 Inhibitors, Metformin, fibrates, statins, insulin, DPP-4 inhibitors and sulfonylurea unless prescribed dose has been stable for the last 6 months prior to the biopsy. 18. Treatment with Valproic acid, Tamoxifen, Methotrexate, Amiodarone or chronic treatment with anti-cholinergic agents, corticosteroids, high dose estrogen and tetracycline within 12 months prior to the screening visit. 19. Chronic treatment with antibiotics (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) >3X the upper limit of normal (UNL). Patients with a reason for CPK elevation may have the measurement repeated prior to randomization; a CPK retest > 3X ULN leads to exclusion. 24. Patients with condition(s) that makes them unsuitable to perform the NMRS (as determined by the PI or the MRI facility). 25. Hypersensitivity to Aramchol or to any of the excipients in the tablets 26. Hypersensitivity to cholic acid or bile acid sequestrants |
Country | Name | City | State |
---|---|---|---|
Chile | Biomedica Research Group | Santiago | |
Chile | Centro de Investigacion Clinica CEIC | Santiago | |
Chile | Hospital Clinico Universidad de Chile | Santiago | |
Chile | Pontificia Universidad Catolica de Chile | Santiago | |
Chile | Centro de Investigaciones Clinicas Vina del Mar | Vina del Mar | |
France | Centre Hospitalier Universitaire (CHU) d'Angers | Angers | |
France | Centre Hospitalier Universitaire Dijon Bourgogne | Dijon | |
France | San Joseph Service Hepato Gastro Entrologie | Marseille | |
France | Hospital Saint Eloi | Montpellier | |
France | CHU Centre Hospiatalier Universitaire de Rennes | Paris | |
France | Hospital Pitie-Salpetriere | Paris | |
France | Hospital Saint-Antoine AP-HP | Paris | |
France | Hopital Paul Brousse | Villejuif | |
Georgia | Unimed Adjara | Batumi | |
Georgia | Clinic Cortex | Tbilisi | |
Georgia | David Tatishvili Medical Center | Tbilisi | |
Georgia | LTD Diacor | Tbilisi | |
Georgia | Research Institute of Clinical Medicine | Tbilisi | |
Germany | Medizinische Hochschule | Hannover | |
Germany | EUGASTRO GmbH | Leipzig | |
Germany | Universitat Leipzig Medizinische Fakultat | Leipzig | |
Hong Kong | Humanity & Health Medical Centre | Central | |
Israel | Carmel Medical Center | Haifa | |
Israel | Rambam Medical Center | Haifa | |
Israel | Hadassah Ein Karem Medical Cente | Jerusalem | |
Israel | Naharia Medical Center | Nahariya | |
Israel | The Holy family Medical Center | Nazareth | |
Israel | Sheba Medical Center | Ramat Gan | |
Israel | Tel-Aviv Saurasky Medical Center | Tel-Aviv | |
Israel | Asaf Harofeh Medical Center | Zrifin | |
Italy | Spedali Civili di Brescia | Brescia | |
Italy | Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico | Milan | |
Italy | A.O. San Paolo | Milano | |
Italy | A.O. U. "Federico II" di Napoli | Napoli | |
Italy | Azienda Ospedaliera di Rilievo Nazionale "A.Cardarelli" | Napoli | |
Italy | Azienda Ospidaliera Universitaria Seconda Universita di Napoli | Napoli | |
Italy | A.O.U. Maggiore della Carità | Novara | |
Italy | "Ospedale Cristo Re" dell'Istituto Figlie di N.S. al Monte Calvario | Roma | |
Italy | Fondazione Policlinico di Tor Vergata | Roma | |
Italy | Ospedale San Camillo | Roma | |
Italy | Policlinico A. Gemelli | Roma | |
Italy | Policlinico Umberto I Di Roma | Roma | |
Italy | Policlinico Univestitario Campus Biomedico | Roma | |
Lithuania | Hospital of Lithuanian University of Health Sciences Kaunas Clinics | Kaunas | |
Lithuania | Klaipeda University Hospital | Klaipeda | |
Lithuania | Vilinius University Hospital Santariskiu Klinikos | Vilnius | |
Mexico | JM Research | Cuernavaca | |
Mexico | Consultorio Médico | Metepec | |
Mexico | Consultorio Medico | Mexico City | |
Mexico | Instituto de Ciencias Medicas y de la Nutricion Salvador Zubiran | Mexico City | |
Mexico | Torre de Consultorios Clinica Londres | Mexico City | |
Mexico | Torre de Consultorios Clinica Londres | Mexico Distrito Federal | |
Mexico | Consultorio Medico del Dr. Mauricio Castillo Barradas | México Distrito Federal | |
Mexico | Accelerium Clinical Research | Monterrey | |
Mexico | Unidad de Hígado Hospital Universitario Dr. José Eleuterio González | Monterrey | Nuevo León |
Mexico | "Angeles Valle oriente" Hospital | San Pedro Garza Garcia | |
Romania | Clinical Institute Colentina | Bucharest | |
Romania | The National Institute for Infectious Diseases "Prof. Dr. Matei Bals", Clinical Department for Adults II | Bucharest | |
Romania | Cluj County Emergency Hospital | Cluj Napoca | |
Romania | TVM Medical | Cluj Napoca | |
Romania | County Hospital Mures-Gastroenterology Department | Targu Mures | |
United States | University of Virginia Medical Center | Charlottesville | Virginia |
United States | Profil Institue for Clinical Research Inc. | Chula Vista | California |
United States | Texas Digestive Disease Consultants | Dallas | Texas |
United States | Duke University Medical Center | Durham | North Carolina |
United States | Brooke Army Medical Center | Fort Sam Houston | Texas |
United States | Indiana University | Indianapolis | Indiana |
United States | Gastroenterology Consultants of San Antonio | Live Oak | Texas |
United States | Cedars-Sinai Medical Center | Los Angeles | California |
United States | Columbia University Medical Center | New York | New York |
United States | Mount Sinai | New York | New York |
United States | California Liver Research Institute | Pasadena | California |
United States | Wake Research | Raleigh | North Carolina |
United States | Inland Empoire Liver Foundation | Rialto | California |
United States | Clinical Trials of Texas | San Antonio | Texas |
United States | Texas Liver Institute San Antonio | San Antonio | Texas |
United States | University of California Department of Medicine Division of Gastroenterology | San Diego | California |
United States | Orange County Research Center | Tustin | California |
Lead Sponsor | Collaborator |
---|---|
Galmed Research and Development, Ltd. | Clinical Reference Laboratory, ClinIntel, Diamond Pharma Services Regulatory Affairs Consultancy, DSG EDC, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Itamar-Medical, Israel, Medical University of Graz, One Way Liver OWL, Sharp Clinical Services, Tel-Aviv Sourasky Medical Center, TransPerfect |
United States, Chile, France, Georgia, Germany, Hong Kong, Israel, Italy, Lithuania, Mexico, Romania,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Change From Baseline to Termination/Early Termination in HbA1C | Change from baseline to Week 52 or Termination visit in Hemoglobin A1C (%) | At baseline until week 52 | |
Primary | Change From Baseline in Mean Liver Fat | absolute % change from baseline to end of study in liver triglycerides to water ratio (fat/water+fat) as measured by MRS | At screening (baseline) and at week 52 | |
Secondary | NASH Resolution Without Worsening of Fibrosis | The endpoint was defined as end of study biopsy, observed under microscope and showing:
Cell Ballooning (special form of liver cell injury associated with cell swelling and enlargement)= 0 Inflammation (presence or absence of cells from the immune system) = 0 or 1 No worsening of fibrosis (scar formation) = increase in fibrosis score by 1 or more point |
At screening and at week 52 | |
Secondary | Fibrosis Improvement Without Worsening of NASH | The endpoint was defined as end of study biopsy showing:
A decrease in fibrosis score = 1 point No worsening of NASH (defined by an increase of inflammation and/or ballooning) |
At screening and at week 52 | |
Secondary | Change From Baseline to Week 52/Termination in ALT | Change from baseline to Week 52 or Termination visit in ALT levels (U/L) | At baseline until week 52 |
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