JKB-121 for the Treatment of Nonalcoholic Steatohepatitis

Phase 2

Completed

• Conditions: Nonalcoholic Steatohepatitis
• Interventions: Drug: Placebo

• Registration Number: NCT02442687
• Lead Sponsor: Manal Abdelmalek

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.

Study Timeline

• Study First Submitted: 2015-04-07
• Study First Submitted QC: 2015-05-12
• Study First Posted: 2015-05-13
• Study Start: 2015-08-01
• Primary Completion: 2017-09-24
• Study Completion: 2017-09-24
• Results First Submitted: 2018-08-24
• Status Verified: 2018-12
• Results First Submitted QC: 2018-12-07
• Last Update Submitted: 2018-12-07
• Results First Posted: 2019-01-07
• Last Update Posted: 2019-01-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 65

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
C	Placebo	Identical appearing placebo

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Number of Subjects With ALT in Normal Range at Week 24	Week 24	Normal range is \<40 U/L
Change in BMI (Body Mass Index)	Baseline, week 24
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
Analysis of ALT Change From Baseline to Week 12 (Per Protocol Population)	Baseline to week 12
Analysis of ALT Change From Baseline to Week 24 (Per Protocol Population)	Baseline to week 24
Time to Remission (in Weeks)	24 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.
Change in Hemoglobin A1C	Baseline, week 24
Percent Change in Cholesterol	Baseline, week 24
Percent Change in Low Density Lipoprotein (LDL) Cholesterol	Baseline, week 24
Change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)	Baseline, week 24	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.
Percent Change in Triglycerides	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
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
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

Trial Locations

Locations (8)

Digestive Associates; 🇺🇸 Las Vegas, Nevada, United States

Duke University; 🇺🇸 Durham, North Carolina, United States

Digestive Disease Specialists of the Southeast; 🇺🇸 Dothan, Alabama, United States

Northwestern University Feinberg School of Medicine; 🇺🇸 Chicago, Illinois, United States

Digestive Disease Specialists; 🇺🇸 Cincinnati, Ohio, United States

Brook Army Medical Center; 🇺🇸 Houston, Texas, United States

University of Virginia Health Systems; 🇺🇸 Charlottesville, Virginia, United States

Medical College of Virginia; 🇺🇸 Richmond, Virginia, United States