JKB-121 for the Treatment of Nonalcoholic Steatohepatitis

A Randomized, Double-Blind, Placebo Controlled, Parallel-Group, Phase II Trial of JKB-121 for the Treatment of Nonalcoholic Steatohepatitis (NASH)

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

Study Overview

• Status: Completed
• Conditions: Nonalcoholic Steatohepatitis
• Intervention / Treatment: Drug: Placebo; Drug: JKB-121: 5 mg twice daily; Drug: JKB-121: 10 mg twice daily

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.

• Study Type: Interventional
• Enrollment (Actual): 65
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Dothan, Alabama, United States, 36305
      • Digestive Disease Specialists of the Southeast
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University Feinberg School of Medicine
  • Nevada
    • Las Vegas, Nevada, United States, 89102
      • Digestive Associates
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Digestive Disease Specialists
  • Texas
    • Houston, Texas, United States, 78234
      • Brook Army Medical Center
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia Health Systems
    • Richmond, Virginia, United States, 23298
      • Medical College of Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: A; JKB 121, 5 mg twice daily	Drug: JKB-121: 5 mg twice daily
Active Comparator: B; JKB 121, 10 mg twice daily	Drug: JKB-121: 10 mg twice daily
Placebo Comparator: C; Identical appearing placebo	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Analysis of MRI-PDFF Change From Baseline to Week 24 (Per Protocol Population)	Baseline to week 24
Analysis of MRI-PDFF Change From Baseline to Week 12 (Per Protocol Population)	Baseline to Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analysis of ALT Change From Baseline to Week 24 (Per Protocol Population)		Baseline to week 24
Analysis of ALT Change From Baseline to Week 12 (Per Protocol Population)		Baseline to week 12
Time to Remission (in Weeks)	Time to remission is the time in weeks from randomization to liver function remission, defined as two consecutive ALT values within normal range (<40 U/L) during the treatment period.	24 weeks
Change in BMI (Body Mass Index)		Baseline, week 24
Change in Hemoglobin A1C		Baseline, week 24
Change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)	HOMA-IR was calculated according to the formula: fasting insulin (microU/L) x fasting glucose (nmol/L)/22.5. Optimal Range: 1.0 (0.5-1.4). Lower values represent a better outcome.	Baseline, week 24
Percent Change in Cholesterol		Baseline, week 24
Percent Change in Triglycerides		Baseline, week 24
Percent Change in Low Density Lipoprotein (LDL) Cholesterol		Baseline, week 24
Percent Change in High Density Lipoprotein (HDL)		Baseline, week 24
Mean Serum Aspartate Aminotransferase (AST)		weeks 4, 8, 12, 16, 20, and 24
Mean Serum Alanine Aminotransferase (ALT)		weeks 4, 8, 12, 16, 20, and 24
Mean Serum Gamma-glutamyl Transpeptidase (GGT)		weeks 4, 8, 12, 16, 20, and 24
Number of Subjects With ALT in Normal Range at Week 24	Normal range is <40 U/L	Week 24
Maximum Observed Concentrations (Cmax)		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
Minimum Observed Concentration (Cmin)		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
Area Under Concentration-time (AUC)		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
Half-life		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

Collaborators and Investigators

• Sponsor: Manal Abdelmalek
• Investigators: Principal Investigator: Manal F Abdelmalek, MD, MPH, Duke University

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2015
• Primary Completion (Actual): September 24, 2017
• Study Completion (Actual): September 24, 2017

Study Registration Dates

• First Submitted: April 7, 2015
• First Submitted That Met QC Criteria: May 12, 2015
• First Posted (Estimate): May 13, 2015

Study Record Updates

• Last Update Posted (Actual): January 7, 2019
• Last Update Submitted That Met QC Criteria: December 7, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: Pro00062677

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No