Trial to Examine the Effect of Two Doses of GRI-0621 in Patients With Chronic Liver Disease

NCT02949375 | Terminated Phase 2 DMC

• 1 other identifier: GRI-0621-201
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

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.

Conditions

Chronic Liver Disease

Outcome Measures

Primary Outcomes (1)

• Change in serum ALT levels from Day 0 (baseline) to Day 28

  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.

  0 and 28 days

Secondary Outcomes (9)

• Change in serum AST levels from Day 0 (baseline) to Day 28

  0 and 28 days

• 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

• 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 peak plasma concentration [Cmax] on Day 7 and Day 28.

  7 and 28 days

Other Outcomes (1)

• Effect, if any, that the investigational product may have on serum triglyceride levels.

  28 days

Study Arms (3)

Placebo Arm

PLACEBO COMPARATOR

Gel capsule containing Placebo to be taken once per day

Drug: Placebo Comparator

4.5mg GRI-0621

ACTIVE COMPARATOR

4.5mg GRI-0621 gel capsule to be taken once per day

Drug: Active Comparator:4.5mg GRI-0621

6mg GRI-0621

ACTIVE COMPARATOR

6mg GRI-0621 gel capsule to be taken once per day

Drug: Active Comparator: 6.0mg GRI-0621

Interventions

Placebo Comparator DRUG

Placebo gel capsule to be taken daily for 28 days

Placebo Arm

Active Comparator:4.5mg GRI-0621 DRUG

4.5mg GRI-0621 gel capsule to be taken daily for 28 days

4.5mg GRI-0621

Active Comparator: 6.0mg GRI-0621 DRUG

6.0mg GRI-0621 gel capsule to be taken daily for 28 days

6mg GRI-0621

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Completion of the written informed consent process for trial participation prior to all trial-related procedures, including HIV testing.
• Male or female participants aged 18 to 65 years.
• 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.
• Female participants of child-bearing potential must have negative serum and urine pregnancy tests at screening and randomization respectively.
• History of chronic liver disease \[CLD\] as a result of viral hepatitis, alcoholic steatohepatitis \[ASH\] or non-alcoholic steatohepatitis \[NASH\].
• 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

You may not qualify if:

• Use of any other investigational drug within 30 days or five half-lives (whichever is longer) of the first dose of GRI-0621.
• Current pregnancy or lactation.
• A history of anaphylaxis or severe hypersensitivity to any drugs.
• A known hypersensitivity to any component of the investigational product or to any other retinoids.
• ALT or AST \> 10 x ULN on any occasion during the screening period (Day -28 to Day -1)
• ALT or AST known to have been \> 10 X ULN on any occasion during the 2 months prior to screening.
• Any of the following laboratory abnormalities at screening:
• Serum creatinine \> 1.5 x ULN
• Hemoglobin \< 10.0 g/L
• Platelets \< 75 x 109/L
• White cell count \< 3.0 x 109/L.
• Known hypothyroidism requiring treatment or laboratory results suggestive of hypothyroidism at screening (thyroxine \[T4\] \< LLN and thyroid-stimulating hormone \[TSH\] \> ULN).
• Any clinically significant ECG abnormalities.
• Current or recent (during the 3 months prior to screening) or required treatment for tuberculosis infection.
• A history of any malignancy (other than treated localized basal cell carcinoma of the skin) in the last 5 years.

Sponsors & Collaborators

• GRI Bio Operations, Inc.: lead

Study Sites (1)

Steve Biko Academic Hospital

Pretoria, Gauteng, 0001, South Africa

Location

Study Officials

• Mpho K Kgomo, MBBCH

  Department Head; Gastroenetrology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 26, 2016
• First Posted: October 31, 2016
• Study Start: September 1, 2015
• Primary Completion: November 1, 2018
• Study Completion: June 1, 2019
• Last Updated: August 9, 2019

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will not share

Locations

ZA (1)