Nonalcoholic Steatohepatitis (NASH)
Conditions
Keywords
fibrosis, liver fibrosis, diabetes, obesity
Brief summary
An Open-Label Part was added: This part will enroll in selected sites which are less affected by the COVID-19 pandemic. 150 subjects with NASH and fibrosis confirmed by liver histology (F1-F3) will be randomized into 3 groups according to the post-baseline biopsy. The objective of the Open-Label Part is: * To evaluate the safety and PK of twice daily administration (BID) of Aramchol 300mg in subjects with NASH and liver fibrosis. * To explore the kinetics of histological outcome measures and Non-Invasive Tests (NITs) associated with NASH and fibrosis for the treatment duration of 24, 48 and 72 weeks. All patients will be allocated to Aramchol. Double Blind Part: This part is double blind, placebo controlled randomized in subjects with NASH and fibrosis stages 2-3 who are overweight or obese and have prediabetes or type 2 diabetes. The primary objectives of this part of the study are to evaluate the effect of Aramchol as compared to placebo on NASH resolution, fibrosis improvement and clinical outcomes related to progression of liver disease. Subjects will be randomized to receive Aramchol 300mg BID or matching placebo in a 2:1 randomization ratio. This double-blind phase of the study will recruit patients once the study will be continued.
Detailed description
A total of 150 subjects, including those already randomized to Aramchol 300 mg BID or Placebo, were to be randomized in a ratio of 1:1:1 to receive Aramchol 300 mg BID in the open-label (OL) part according to the grouping below: Group A: The post-baseline liver biopsy was to be conducted at Week 24 Group B: The post-baseline liver biopsy was to be conducted at Week 48 Group C: The post-baseline liver biopsy was to be conducted at Week 72 In order to more comprehensively explore the kinetics of histological outcome measures (e.g., are there subjects who did not show improvement in outcome at Weeks 24, 48, or 72, but improved with longer duration of treatment), a second post-baseline liver biopsy sample was to be collected for subjects whose post-baseline liver biopsy at Weeks 24 or 48, or 72 did not show at least one stage improvement in fibrosis (fibrosis non-responders). The second post-baseline liver biopsy sample was to be collected one year later (i.e., at Weeks 72 or 96 or 120, respectively). Subjects already randomized and ongoing in the PC part were given the option to switch to the OL part
Interventions
Aramchol 300 mg BID
DRUGPlacebo
Placebo BID
Sponsors
Galmed Research and Development, Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
In the Open Label part of the study, there will be a single group of 150 subjects (expected) all receiving Aramchol 300mg BID.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Male or female age 18 to 75 years 2. Histological confirmation of NASH on a diagnostic liver biopsy by central reading of the slides (biopsy obtained within 6 months prior to randomization or during the screening period) 3. Total NAS Score 4 or more with at least 1 in each component of the NAS Score (steatosis ≥1 AND inflammation ≥1 AND ballooning ≥1) 4. Fibrosis Stage must be 2 or 3 (Open-Label Part may include up to 30 subjects with fibrosis stage 1) 5. Body mass index (BMI) between 25kg/m2 and 40 kg/m2 (Open Label part: BMI \<40 kg/m2) 6. AST\>20 IU/L 7. Type 2 diabetes mellitus or prediabetes (Open Label Part only: Type 2 diabetes or prediabetes is not an inclusion criteria) 8. For subjects with type 2 diabetes, glycemia must be controlled 9. Females of childbearing potential must practice a highly effective method of contraception throughout the study period and for 1 month after treatment discontinuation. 10. Able to understand the nature of the study and to provide signature of the written informed consent. Key
Exclusion criteria
1. Histologically documented liver cirrhosis (fibrosis stage 4) 2. Inability or unwillingness to undergo a liver biopsy 3. Abnormal synthetic liver function 4. ALT or AST \>5× upper limit of normal (ULN) 5. Platelet count \< 150,000mm3 6. Alkaline phosphatase ≥2× ULN 7. Known or suspected hepatocellular carcinoma (HCC) 8. Model for End-Stage Liver Disease (MELD) score \> 12 9. Prior history or presence of decompensated liver disease 10. Other (acute or chronic) coexisting liver disease based on medical history and/or centralized review of liver histology) 11. Known alcohol and/or any other drug abuse or dependence in the last five years 12. Weight loss of more than 5% within 3 months prior to screening 13. History of bariatric surgery within 5 years of liver biopsy or planned surgery for weight reduction 14. Treatment with drugs that may cause NAFLD within 12 months prior to liver biopsy 15. Treatment with some anti-diabetic medications; Unless started prior to biopsy (timeframe depending on drug) and stable 16. Current or planned treatment with immunosuppressive drugs 17. Evidence of any other unstable or untreated clinically significant disease 18. Uncontrolled hypertension 19. Any other condition that in the opinion of the Investigator warrants exclusion from the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Open Label Part: Improvement of Fibrosis Based on Liver Biopsy | Up to 72 or 120 weeks | Improvement of fibrosis was defined by the following: 1. One stage or more reduction in fibrosis stage as assesed by the NASH-CRN classification 2. Ranked paired assessment between post-baseline compared to baseline biopsies (i,proved, worsened or stable fibrosis) 3. Reduction in the the continous phenotypic Fibrosis composite severity (Ph-FCS) score ≥0.3 in absolute value or ≥25% in relative value |
| Double Blind Part: To Evaluate the Effect of Aramchol Compared to Placebo on Liver Histology by Assessing the Following Primary Endpoints. Study Was Suspended and Thus Results Are Expected 2027 | 72 weeks | * Resolution of NASH defined as the Proportion (%) of subjects with resolution of NASH (defined by Ballooning of 0 and inflammation 0-1) and no worsening of liver fibrosis, or * Improvement in Fibrosis defined as the Proportion (%) of subjects with improvement in liver fibrosis greater than or equal to one stage and no worsening of steatohepatitis. |
| Double Blind Part: To Evaluate the Effect of Aramchol Compared to Placebo on Composite Long-term Outcome Study Was Suspended so Results Expected 2027 | at End of Study, latest at 5 years from last subject's randomization | Proportion (%) of subjects experiencing at least 1 of the following events: All-cause mortality, Liver transplant, Histological progression to cirrhosis, MELD score \>15, Hospitalization due to hepatic decompensation event(s). |
Countries
United States
Contacts
STUDY_DIRECTORYossi Gilgun-Sherki, PhD, MBA
Executive Drug Development Consultant
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ARCON ITT All subjects who were randomized to Aramchol | 157 |
| Total | 157 |
Baseline characteristics
| Characteristic | ARCON ITT |
|---|---|
| Age, Continuous | 58.1 Years STANDARD_DEVIATION 10.2 |
| Biopsy evaluation based on NASH CRN Baseline CRN fibrosis stage- F1 | 33 Participants |
| Biopsy evaluation based on NASH CRN Baseline CRN fibrosis stage- F2 | 34 Participants |
| Biopsy evaluation based on NASH CRN Baseline CRN fibrosis stage- F3 | 76 Participants |
| Biopsy evaluation based on NASH CRN Baseline CRN fibrosis stage- F4 | 8 Participants |
| Biopsy evaluation based on NASH CRN Not reported | 6 Participants |
| Body mass index (kg/m2) | 32.7 Kg/ M2 STANDARD_DEVIATION 4.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 28 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 127 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| NAS score | 5.0 units on a scale STANDARD_DEVIATION 1.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 15 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 134 Participants |
| Region of Enrollment Australia | 4 participants |
| Region of Enrollment Belgium | 3 participants |
| Region of Enrollment Canada | 5 participants |
| Region of Enrollment Chile | 6 participants |
| Region of Enrollment France | 5 participants |
| Region of Enrollment Israel | 2 participants |
| Region of Enrollment Mexico | 7 participants |
| Region of Enrollment South Korea | 10 participants |
| Region of Enrollment Spain | 5 participants |
| Region of Enrollment Turkey | 25 participants |
| Region of Enrollment United Kingdom | 1 participants |
| Region of Enrollment United States | 84 participants |
| Sex: Female, Male Female | 119 Participants |
| Sex: Female, Male Male | 38 Participants |
| Weight (kg) | 89 Kg STANDARD_DEVIATION 15.2 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 154 / 154 |
| other Total, other adverse events | 27 / 154 |
| serious Total, serious adverse events | 1 / 154 |
Outcome results
Primary
Double Blind Part: To Evaluate the Effect of Aramchol Compared to Placebo on Composite Long-term Outcome Study Was Suspended so Results Expected 2027
Proportion (%) of subjects experiencing at least 1 of the following events: All-cause mortality, Liver transplant, Histological progression to cirrhosis, MELD score \>15, Hospitalization due to hepatic decompensation event(s).
Time frame: at End of Study, latest at 5 years from last subject's randomization
Primary
Double Blind Part: To Evaluate the Effect of Aramchol Compared to Placebo on Liver Histology by Assessing the Following Primary Endpoints. Study Was Suspended and Thus Results Are Expected 2027
* Resolution of NASH defined as the Proportion (%) of subjects with resolution of NASH (defined by Ballooning of 0 and inflammation 0-1) and no worsening of liver fibrosis, or * Improvement in Fibrosis defined as the Proportion (%) of subjects with improvement in liver fibrosis greater than or equal to one stage and no worsening of steatohepatitis.
Time frame: 72 weeks
Primary
Open Label Part: Improvement of Fibrosis Based on Liver Biopsy
Improvement of fibrosis was defined by the following: 1. One stage or more reduction in fibrosis stage as assesed by the NASH-CRN classification 2. Ranked paired assessment between post-baseline compared to baseline biopsies (i,proved, worsened or stable fibrosis) 3. Reduction in the the continous phenotypic Fibrosis composite severity (Ph-FCS) score ≥0.3 in absolute value or ≥25% in relative value
Time frame: Up to 72 or 120 weeks
Population: 51 subjects performed a Baseline and post-baseline biopsy
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Aramchol | Open Label Part: Improvement of Fibrosis Based on Liver Biopsy | Fibrosis improvement NASH-CRN≥1 stage | 31.4 percentage of participants improving |
| Aramchol | Open Label Part: Improvement of Fibrosis Based on Liver Biopsy | NASH resolution without worsening of fibrosis | 26.5 percentage of participants improving |
| Aramchol | Open Label Part: Improvement of Fibrosis Based on Liver Biopsy | Fibrosis improvement by ranked assessment | 51.0 percentage of participants improving |
| Aramchol | Open Label Part: Improvement of Fibrosis Based on Liver Biopsy | Fibrosis improvement (absolute FCS score reduction ≥0.3 | 74.5 percentage of participants improving |
| Aramchol | Open Label Part: Improvement of Fibrosis Based on Liver Biopsy | Fibrosis improvement (relative FCS reduction by ≥25% AI cutoff) | 41.2 percentage of participants improving |