A Clinical Trial to Evaluate the Efficacy and Safety of Two Aramchol Doses Versus Placebo in Patients With NASH

Liver Diseases Clinical Trial

— Aramchol_005  

Official 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02279524
• Other study ID #: Aramchol005
• Status: Completed
• Phase: Phase 2
• Start date: April 29, 2015
• Est. completion date: May 22, 2018

Study information

• Verified date: June 2021
• Source: Galmed Pharmaceuticals Ltd
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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)).

Description:

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: at screening (visit 1(weeks -4 - 0)), baseline (visit 2 (day 0)), visit 3 (week 2), visit 4 week 4), visit 5 (week 8), visit 6 (week 12), visit 7 (week 24), visit 8 (week 32), visit 9 (week 40) and visit 10 (week 52 - (End of Treatment/early termination visit)). 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)).

During the screening period, the severity of the disease will be evaluated with blood tests, liver biopsy and NMRS.

During the study the following assessments will be performed:

• Vital signs will be measured at each study visit.

• A physical examination will be performed at the screening visit, 24 weeks, End of Treatment/early termination and week 65 visit.

The following blood tests will be performed: complete blood count (CBC), serum chemistry (including electrolytes, liver enzymes, direct and total bilirubin, glucose, lipid profile which include triglyceride, cholesterol, HDL, LDL and VLDL, CPK, creatinine, urea, albumin, alkaline phosphatase), ESR and urinalysis during the screening visit, baseline, week 2, 4, 8, 24, 40, 52 and 65 (end of follow up) visits. Serology (HBV, HCV and HIV) will be performed during the screening visit. Coagulation (fibrinogen, PT/INR, aPTT) will be measured during screening and at baseline, week 24, End of Treatment/early termination and week 65 visits. Insulin (HOMA) will be measured during the screening, at week 24 and End of Treatment/early termination visits. HbA1C will be measured during the screening, at week 8, 24, 40 and End of Treatment/early termination visits. C reactive protein, Leptin and Adiponectin will be measured during baseline visit and at end of treatment period. The blood samples taken at these visits, will be tested for possible biomarkers. TSH, T3 and T4 will be measured during the screening visit. beta-hCG in women of childbearing potential will be performed during the screening visit. A serum sample will be collected and kept frozen until study end in case special investigation needs to be performed. This sample will be collected during the screening and visit 10/Early Termination.

• Body weight and waist circumference will be measured in screening, baseline, week 24, end of treatment and week 65 visits. Height will be measured during the screening visit.

• ECG will be performed during the screening visit, visit 7 (week 24) and end of treatment visits.

• All subjects will undergo two NMRS scans, at screening and end of treatment visits.

• FibroMax test will be performed only if the investigator thinks it is necessary

• Liver biopsy will be conducted during the screening and end of treatment visit. The biopsy in the screening visit will be performed only if it was not done within the 6 months prior to this visit.

• Metabolomics blood test will be performed at the screening, visit 7 and the End-of-Treatment/Early Termination visits. From some consenting patients (about 15) a sample from the liver biopsy will be taken for analysis.

• Endothelial Function will be conducted in selected sites. The test will be conducted during the baseline visit before the study treatment will be given and End of Treatment/early termination visit.

• Blood sample for Aramchol trough level will be collected (pre-dose) from patients in Israel at baseline (visit 2) week 4 (visit 4), week 12 (visit 6), week 24 (visit 7), week 40 (visit 9), end of treatment (visit 10) and follow up (visit 11). At selected sites in Mexico, USA and Hong Kong one blood sample will be collected (pre-dose) on visit 4 (up to 10 subjects per country) to test for trough Aramchol blood level differences between populations (e.g., African American, Asian, Hispanic).

• Blood sample for gene analysis will be taken from all consenting patients during the baseline visit, will be kept frozen and analyzed only at the study end.

• Life style questionnaire will be completed at all visits.

• Adverse events will be monitored throughout the study.

• Concomitant Medications will be monitored throughout the study.

• Telephone contacts will be performed on week 16, 20, 28, 36, 44 and 48. An interim safety analysis will be conducted as soon as 120 subjects will completed the follow up period of 24 weeks under study treatment. An independent DSMB will analyze the safety data and recommend a continued course of action. All patients will continue to be treated under the study protocol until conclusion of the analysis will be known.

Safety assessment will include frequency and severity of treatment-emergent AEs, clinically significant laboratory abnormalities, ECG changes and physical examination findings.

Recruitment information / eligibility

• 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

Related Conditions & MeSH terms

• Fatty Liver
• Fibrosis
• Liver Cirrhosis
• Liver Diseases
• Liver Fibroses
• Non-alcoholic Fatty Liver Disease
• Non-Alcoholic Steatohepatitis

Intervention

Drug:
• Aramchol
Subjects will be administered Aramchol as follows: One tablet of Aramchol 400 mg and one tablet of matching placebo for Aramchol. One tablet of Aramchol 400 mg and one tablet of Aramchol 200 mg. Two tablet of Aramchol matching placebo. The tablets should be taken orally in the morning within 30 min after breakfast with a glass of water (250 ml). Subjects are allowed to omit study drugs up to 3 consecutive days during the study.

Locations

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

Sponsors (12)

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

Countries where clinical trial is conducted

United States,  Chile,  France,  Georgia,  Germany,  Hong Kong,  Israel,  Italy,  Lithuania,  Mexico,  Romania, 

Outcome

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

External Links

•   The Fatty Acid-Bile Acid Conjugate Aramchol Reduces Liver Fat Content in Patients With Nonalcoholic Fatty Liver Disease