Clinical trial NCT02442687: JKB-121 for the Treatment of Nonalcoholic Steatohepatitis
Official title: A Randomized, Double-Blind, Placebo Controlled, Parallel-Group, Phase II Trial of JKB-121 for the Treatment of Nonalcoholic Steatohepatitis (NASH)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Nonalcoholic Steatohepatitis
Lead sponsor: Duke University
Sponsor class: OTHER
First posted: 2015-05-13
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To evaluate the safety and potential efficacy of two dose levels of JKB-121 (5 mg twice daily and 10 mg twice daily) in reducing liver fat and/or liver biochemistry compared to placebo in patients with biopsy-proven nonalcoholic steatohepatitis

Detailed description: JKB-121 is a long-acting small molecule that is efficacious as a weak antagonist at the TLR-4 receptor. It is a non-selective opioid antagonist which has been shown to prevent the lipopolysaccharide (LPS) induced inflammatory liver injury in a methionine/choline deficient diet fed rat model of nonalcoholic fatty liver disease. In vitro, JKB-121 neutralized or reduced the LPS-induced release of inflammatory cytokines, deactivated hepatic stellate cells, inhibited hepatic stellate cell proliferation, and collagen expression. Inhibition of the TLR4 signaling pathway may provide an effective therapy in the prevention of inflammatory hepatic injury and hepatic fibrosis in patients with nonalcoholic steatohepatitis. This study will evaluate the safety and potential efficacy of two dose levels of JKB-121 (5 mg twice daily and 10 mg twice daily) in reducing liver fat and/or liver biochemistry compared to placebo in patients with biopsy-proven nonalcoholic steatohepatitis.

Eligibility criteria: Inclusion Criteria:

1. Age ≥ 18 years
2. Provision of written informed consent
3. Biopsy-proven NASH within 12 months or at screening
4. ALT \> 40 U/L for women and \> 60 U/L for men at screening and at least once in the previous 12 months.
5. HBA1C of ≤ 9.0

Exclusion Criteria:

1. Any chronic liver disease other than NASH
2. Cirrhosis, as assessed clinically or histologically
3. Presence of vascular liver disease
4. BMI ≤ 25 kg/m2
5. Excessive alcohol use (\> 20 g/day) within the past 2 years
6. AST or ALT \> 250 U/L.
7. Type 1 diabetes mellitus
8. Bariatric surgery in the past 5 years.
9. Weight gain of \> 5% in past 6 months or \> 10% change in past 12 months.
10. Contraindication to MRI
11. Inadequate venous access
12. HIV antibody positive, hepatitis B surface antigen positive (HBsAg), or Hepatitis C virus (HCV) RNA positive.
13. Receiving an elemental diet or parenteral nutrition
14. Chronic pancreatitis or pancreatic insufficiency
15. Any history of complications of cirrhosis
16. Concurrent conditions:

    * Inflammatory bowel disease
    * Significant cardiac disease
    * chronic infection or immune mediated disease
    * Any malignant disease
    * Prior solid organ transplant
    * Any other concurrent condition which, in the opinion of the investigator, could impact adversely on the subject participating or the interpretation of the study data.
17. Concurrent medications which may treat NASH
18. HbA1C \> 9.0%
19. Pregnancy or breastfeeding.

Primary outcomes:
measure: Analysis of MRI-PDFF Change From Baseline to Week 24 (Per Protocol Population)
timeFrame: Baseline to week 24
measure: Analysis of MRI-PDFF Change From Baseline to Week 12 (Per Protocol Population)
timeFrame: Baseline to Week 12
Secondary outcomes:
measure: Analysis of ALT Change From Baseline to Week 24 (Per Protocol Population)
timeFrame: Baseline to week 24
measure: Analysis of ALT Change From Baseline to Week 12 (Per Protocol Population)
timeFrame: Baseline to week 12
measure: Time to Remission (in Weeks)
timeFrame: 24 weeks
measure: Change in BMI (Body Mass Index)
timeFrame: Baseline, week 24
measure: Change in Hemoglobin A1C
timeFrame: Baseline, week 24
measure: Change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)
timeFrame: Baseline, week 24
measure: Percent Change in Cholesterol
timeFrame: Baseline, week 24
measure: Percent Change in Triglycerides
timeFrame: Baseline, week 24
measure: Percent Change in Low Density Lipoprotein (LDL) Cholesterol
timeFrame: Baseline, week 24
measure: Percent Change in High Density Lipoprotein (HDL)
timeFrame: Baseline, week 24
measure: Mean Serum Aspartate Aminotransferase (AST)
timeFrame: weeks 4, 8, 12, 16, 20, and 24
measure: Mean Serum Alanine Aminotransferase (ALT)
timeFrame: weeks 4, 8, 12, 16, 20, and 24
measure: Mean Serum Gamma-glutamyl Transpeptidase (GGT)
timeFrame: weeks 4, 8, 12, 16, 20, and 24
measure: Number of Subjects With ALT in Normal Range at Week 24
timeFrame: Week 24
measure: Maximum Observed Concentrations (Cmax)
timeFrame: pre-dose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10, 12, and 24 hours
measure: Minimum Observed Concentration (Cmin)
timeFrame: pre-dose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10, 12, and 24 hours
measure: Area Under Concentration-time (AUC)
timeFrame: pre-dose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10, 12, and 24 hours
measure: Half-life
timeFrame: pre-dose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10, 12, and 24 hours
Other outcomes:
Locations:
city: Dothan
country: United States
facility: Digestive Disease Specialists of the Southeast
state: Alabama
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Las Vegas
country: United States
facility: Digestive Associates
state: Nevada
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cincinnati
country: United States
facility: Digestive Disease Specialists
state: Ohio
city: Houston
country: United States
facility: Brook Army Medical Center
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health Systems
state: Virginia
city: Richmond
country: United States
facility: Medical College of Virginia
state: Virginia
Study officials:
affiliation: Duke University
name: Manal F Abdelmalek, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References: