Chronic Liver Disease
Conditions
Brief summary
Primary objectives: To evaluate the change in serum alanine transaminase \[ALT\] levels from Day 0 to Day 28, following daily doses of 4.5 or 6mg of GRI-0621 compared to placebo, in patients with chronic liver disease and elevated serum levels of ALT. Serum ALT level will be used as a marker of liver inflammation. To assess the safety and tolerability of GRI-0621 at these two doses. Secondary objectives: To assess the change in serum aspartate transaminase \[AST\] levels from baseline to Day 28, following daily doses of 4.5 or 6mg of GRI-0621 or matching placebo, in patients with chronic liver disease and elevated serum levels of AST. Serum AST level will be used as a second marker of liver inflammation. To evaluate the response to 4.5mg GRI-0621 versus 6mg GRI-0621 in terms of the change in serum ALT levels from baseline measured at the different trial time points. To assess changes in serum cytokeratin 18 \[CK-18\] levels from baseline to Day 28, following daily doses of 4.5 or 6mg of GRI-0621 or matching placebo, in patients with chronic liver disease. Serum CK-18 is used as a marker of hepatocyte cell death due to either necrosis or apoptosis. To measure Natural Killer T lymphocyte \[NKT\] cell activity at baseline and at Day 28 following daily doses of 4.5 or 6mg of GRI-0621 or matching placebo. To describe the steady-state pharmacokinetics \[PK\] of GRI-0621 in patients with chronic liver disease. Exploratory objectives: To assess the effect, if any, that the investigational product may have on serum triglyceride levels.
Detailed description
This is a multi- centre, double-blind, randomized, placebo-controlled phase 2a trial in participants aged 18 to 65 years with chronic liver disease. It is designed to assess the safety, tolerability and efficacy of both 4.5mg and 6mg of GRI-0621 when administered once daily for 28 days. A total of 60 participants will be randomised to received 4.5mg or 6mg of GRI-0621 or matching placebo in a 1:1:1 ratio. The investigational product will be administered orally once daily in the morning for a duration of 28 days. Participants will return to the clinic for follow-up safety and efficacy assessments on Days 7, 14, 21 and 28. Additionally, PK sampling will be performed on Days 7 and 28, and samples for immunological assays to assess the activity of NKT cells will be drawn on Days 0 (baseline) and 28. An end-of-trial follow-up visit will be performed 14 days after the last dose of the investigational product on Day 42. The primary efficacy objective will be measured by the change from baseline to Day 28 in serum ALT levels. The baseline ALT level will be calculated as the mean of the Day -7 to -1 and Day 0 serum ALT results. Safety and tolerability will be measured by the incidence and severity of adverse events and changes in physical examination findings, physical measurements, vital signs, ECG findings and standard laboratory safety parameters (including hematology, clinical chemistry, coagulation parameters and urinalysis).
Interventions
DRUGPlacebo Comparator
Placebo gel capsule to be taken daily for 28 days
DRUGActive Comparator:4.5mg GRI-0621
4.5mg GRI-0621 gel capsule to be taken daily for 28 days
DRUGActive Comparator: 6.0mg GRI-0621
6.0mg GRI-0621 gel capsule to be taken daily for 28 days
Sponsors
GRI Bio Operations, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
A participant will be eligible for participation in the trial if all of the following inclusion criteria are met: 1. Completion of the written informed consent process for trial participation prior to all trial-related procedures, including HIV testing. 2. Male or female participants aged 18 to 65 years. 3. Female participants of child-bearing potential must practice an effective method of birth control from four weeks prior to randomization and agree to continue this until 6 months after the completion of the end-of-trial follow-up visit. Effective birth control must include two methods, one of which must be a barrier method. Female participants are considered not to be of child-bearing potential if they are post-menopausal (12 months of spontaneous amenorrhoea with an appropriate clinical profile, or 6 months of spontaneous amenorrhoea with local laboratory serum follicle-stimulating hormone \[FSH\] levels in keeping with post-menopause) or surgically sterile (after bilateral oophorectomy, hysterectomy or salpingectomy). For the purpose of this trial any participant who has had a tubal ligation will not be considered surgically sterile due to the teratogenic nature of this class of chemical entities. 4. Female participants of child-bearing potential must have negative serum and urine pregnancy tests at screening and randomization respectively. 5. History of chronic liver disease \[CLD\] as a result of viral hepatitis, alcoholic steatohepatitis \[ASH\] or non-alcoholic steatohepatitis \[NASH\]. 6. Evidence of viral hepatitis, ASH or NASH as described beneath: * Viral Hepatitis: * Hepatitis C virus \[HCV\] infection as confirmed by the presence of HCV RNA (determined by PCR) and no other cause of liver disease or * Hepatitis B virus \[HBV\] infection as confirmed by the presence of HBV DNA \> 104 copies/ml (determined by the Roche COBA TaqMan HBV DNA assay) and no other cause for liver disease or * Hepatitis C and B co-infection (as defined above) OR * ASH: * Findings and history consistent with the diagnosis of ASH in the opinion of the investigator OR * NASH: * Absence of viral hepatitis and * A history of no or minimal alcohol use and * Findings and history consistent with the diagnosis of NASH in the opinion of the investigator 7. Body Mass Index (BMI) of 18 to 39kg/m2. 8. Weight ≥ 45kg 9. ALT \> 1.5 x ULN but less than 10 x ULN on two occasions during the screening period (Day -28 to Day -1). The second occasion must be between Day -7 and Day -1. 10. An ability to communicate well with the investigator and to understand and comply with the requirements of the trial. 11. Agree to stay in contact with the trial site for the duration of the trial, provide updated contact information as necessary.
Exclusion criteria
A participant will not be eligible for trial participation if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in serum ALT levels from Day 0 (baseline) to Day 28 | 0 and 28 days | To evaluate the change in serum ALT levels from baseline to Day 28, following daily doses of 4.5 or 6mg of GRI-0621 compared to placebo, in patients with chronic liver disease and elevated serum levels of ALT. Serum ALT level will be used as a marker of liver inflammation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in serum AST levels from Day 0 (baseline) to Day 28 | 0 and 28 days | To assess the change in serum AST levels from baseline to Day 28, following daily doses of 4.5 or 6mg of GRI-0621 or matching placebo, in patients with chronic liver disease and elevated serum levels of AST. Serum AST level will be used as a second marker of liver inflammation. |
| Response to 4.5mg GRI-0621 versus 6mg GRI-0621 in terms of the change in serum ALT levels from Day 0 (baseline) measured at the different trial time points. | 0 and 28 days | — |
| Changes in serum cytokeratin 18 (CK-18) levels from Day 0 (baseline) to Day 28, | 0 and 28 days | To assess changes in serum cytokeratin 18 (CK-18) levels from Day 0 to Day 28, following daily doses of 4.5 or 6mg of GRI-0621 or matching placebo, in patients with chronic liver disease. Serum CK-18 is used as a marker of hepatocyte cell death due to either necrosis or apoptosis. |
| NKT cell activity measured by multi-color flow cytometry at Day 0 (baseline) and at Day 28 following daily doses of 4.5 or 6mg of GRI-0621 or matching placebo. | 0 and 28 days | — |
| Measurement of GRI-0621 time to reach Cmax [Tmax]. | 7 and 28 days | — |
| Measurement of GRI-0621 half life [t1/2] | 7 and 28 days | — |
| Measurement of GRI-0621 clearance [CL] on Days 7 and 28 | 7 and 28 days | — |
| Measurement of GRI-0621 volume of distribution [Vd] on Days 7 and 28 | 7 and 28 days | — |
| Measurement of GRI-0621 peak plasma concentration [Cmax] on Day 7 and Day 28. | 7 and 28 days | — |
Other
| Measure | Time frame |
|---|---|
| Effect, if any, that the investigational product may have on serum triglyceride levels. | 28 days |
Countries
South Africa
Outcome results
None listed