Clinical Trials Register

Summary
EudraCT Number:	2014-003107-29
Sponsor's Protocol Code Number:	Aramchol005
National Competent Authority:	Lithuania - SMCA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-05-31
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Lithuania - SMCA

A.2

EudraCT number

2014-003107-29

A.3

Full title of the trial

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).

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A placebo-controlled clinical trial to evaluate the efficacy and safety of two Aramchol doses in patients with Non-Alcoholic- Steatohepatitis (NASH).

A.3.2

Name or abbreviated title of the trial where available

ARREST

A.4.1

Sponsor's protocol code number

Aramchol005

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02279524

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	GALMED Pharmaceuticals LTD.
B.1.3.4	Country	Israel
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	GALMED Pharmaceuticals LTD.
B.4.2	Country	Israel
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Clinical Accelerator Ltd.
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	First Floor, 10-12 Prospect Hill
B.5.3.2	Town/ city	Douglas, Isle of Man
B.5.3.3	Post code	IM1 1EJ
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+37061831848
B.5.5	Fax number	+37037388466
B.5.6	E-mail	r.minkute@clinicalaccelerator.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Arachidyl amido cholanoic acid 200mg
D.3.2	Product code	Aramchol 200mg
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Arachidyl amido cholanoic acid
D.3.9.1	CAS number	246529-22-6
D.3.9.2	Current sponsor code	Aramchol
D.3.9.3	Other descriptive name	Aramchol
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Arachidyl amido cholanoic acid 400mg
D.3.2	Product code	Aramchol 400mg
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Arachidyl amido cholanoic acid
D.3.9.1	CAS number	246529-22-6
D.3.9.2	Current sponsor code	Aramchol
D.3.9.3	Other descriptive name	Aramchol
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	400
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Non-alcoholic Steatohepatitis in patients with two additional features of metabolic syndrome -overweight or obesity and Diabetes Mellitus type II or pre-diabetes.

E.1.1.1

Medical condition in easily understood language

Fatty liver associated with inflammation and lesions.

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
E.1.2	Level	PT
E.1.2	Classification code	10053219
E.1.2	Term	Non-alcoholic steatohepatitis
E.1.2	System Organ Class	10019805 - Hepatobiliary disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

1. To evaluate the efficacy of Aramchol on NASH resolution by liver biopsy.
2. To evaluate the efficacy of Aramchol on disease activity as measured by NAS/SAF score.
3. To evaluate the effect of Aramchol on metabolic parameters.
4. To compare two doses in order to choose the optimal dose for pivotal Phase III studies.
5. To assess Aramchol’s effect on NASH activity by non-invasive diagnostic methods.
6. To validate new non-invasive tests for the diagnostic and assessments of Aramchol’s effect.
7. To evaluate the safety of Aramchol treatment.
8. To conduct blood trough level of Aramchol.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Genetic
Version/Date: Amendment3 17/01/2015
Title: Correlation of the response to Aramchol treatment and the PNPLA3 genotype.
Objective: To determine if there is an association between PNPLA3 rs738409 genotype and the response of the patients to Aramchol treatment.

E.3

Principal inclusion criteria

1. Male or female age 18 to 75 years.
2. 25 ≤ BMI ≤40 kg/m2 or waist circumference > 88 <200 cm for women and > 102 <200 cm for men.
3. Known type II Diabetes Mellitus or pre-Diabetes according to American Diabetes Association. One of the following 3 criteria is needed for pre-Diabetic: 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%.
4. Histologically proven Steatohepatitis on a diagnostic liver biopsy performed within 6 months before screening visit, confirmed by central laboratory reading of the slides (steatosis > 5% + lobular inflammation, any ballooning, any amount).
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 >3.5g/l, INR 0.8-1.3).
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). If barrier methods are used, it is recommended to practice two methods (e.g. male condom + female diaphragm with spermicide). For country-specific requirements (e.g. Germany) contraception failure rates (Pearl Index) should be under 1% in accordance with the recommendations of the CTFG Working Group on Contraception.
11. Hypertensive patients must be well controlled by stable dose of anti-hypertensive medication for at least 2 months prior to screening (and the stable dose can be maintained throughout the study).
12. Patients previously treated with vitamin E (>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 up to the end of study unless on stable dose for the last 12 months prior to biopsy.
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 metformin, sulfonylurea and insulin are authorized. sulfonylurea and insulin are permitted if glycaemia is self-monitored by the patient.

E.4

Principal exclusion criteria

1. Patients with other active (acute or chronic) liver disease other than NASH (e.g. viral hepatitis, genetic hemochromatosis, Wilson disease, alpha 1antitripsin deficiency, alcohol liver disease, drug induced liver disease) at the time of randomization.
2. Patients who have 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.
5. Patients with familial hypertriglyceridemia and familial 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 (IDB); previous intestinal (ileal or colonic) operation; chronic pancreatic; celiac disease or previous vagotomy.
7. Patients with heart or brain pacemaker.
8. History of surgery within three months of screening which involved stent transplant or any other surgery which includes transplantation 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 blood pressure.
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: DPP-4 inhibitors unless it was stopped 6 months before biopsy,GLP-1 receptor agonists (such as Januvia [Sitagliptin], Byetta [Incretin], etc.) unless it was started at least 12 months and on stable dose over 6 months prior biopsy is taken. In case GLP-1 receptor agonist being stopped, it should be at least 6 months prior to biopsy, as per medical history.
17. Metformin, fibrates, statins, insulin, sulfonylurea unless the dose has been stabilized for the last 6 months prior to the screening visit.
18. Treatment with Valproic acid, Tamoxifen, Methotraxete, Amiodarone or chronic treatment with anti-cholinergic agents 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) >3X the upper limit of normal (ULN). Patients with an intermittent CPK elevation may have the repeated measurement prior to randomization; a CPK retest > 3X ULN leads to exclusion.

E.5 End points

E.5.1

Primary end point(s)

% change from baseline in liver triglycerides concentration measured by NMRS at the end of study.

E.5.1.1

Timepoint(s) of evaluation of this end point

At screening and at week 52.

E.5.2

Secondary end point(s)

1. Improvement in NASH activity index, as measured by NAFLD Activity Score (NAS) or SAF defined as at least two points improvement contributed by more than one parameter without worsening fibrosis.
2. Resolution of steatohepatitis, without worsening of fibrosis (Worsening of fibrosis will be evaluated using NASH CRN [Clinical Research Network] fibrosis staging system. (Resolution means disappearance of ballooning).
3. Changes from baseline in ALT levels.
4. Changes from baseline in insulin resistance, measured by HOMA score.
5. Changes from baseline in HbA1c levels.
6. Changes from baseline in Adiponectin level and Leptin: Adiponectin ratio (LAR).
7. Changes from baseline in inflammation and fibrosis biomarkers: Fibrinogen, CK-18, C-reactive protein (CRP), TNFα, IL 6 and fibrosis Tests (NFS).
8. Changes from baseline in body weight and in waist circumference.
9. Aramchol blood trough level.

E.5.2.1

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 and at the end of the study.
6. At screening and at week 52.
7. At screening and at week 52.
8. At screening, baseline, week 24, week 52, week 65, and unscheduled if applies.
9. At visit 4, visit 6, visit 7, visit 9, visit 10.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Chile

France

Georgia

Germany

Hong Kong

Israel

Italy

Lithuania

Mexico

Romania

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

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:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

240

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After treatment period the patients will be controlled for a follow-up period of 13 weeks without administration of treatment. Since the enrolled patient belong to the pool of the investigational site, it is foreseen that they will continue the treatment for NASH according to the standard site clinical practice.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-07-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-06-29

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-05-22

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