JKB-121 for the Treatment of Nonalcoholic Steatohepatitis

Nonalcoholic Steatohepatitis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02442687
• Other study ID #: Pro00062677
• Status: Completed
• Phase: Phase 2
• Start date: August 1, 2015
• Est. completion date: September 24, 2017

Study information

• Verified date: December 2018
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 65
• Est. completion date: September 24, 2017
• Est. primary completion date: September 24, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Fatty Liver
• Non-alcoholic Fatty Liver Disease
• Nonalcoholic Steatohepatitis

Intervention

Drug:
• JKB-121: 5 mg twice daily

• JKB-121: 10 mg twice daily

• Placebo

Locations

Country	Name	City	State
United States	University of Virginia Health Systems	Charlottesville	Virginia
United States	Northwestern University Feinberg School of Medicine	Chicago	Illinois
United States	Digestive Disease Specialists	Cincinnati	Ohio
United States	Digestive Disease Specialists of the Southeast	Dothan	Alabama
United States	Duke University	Durham	North Carolina
United States	Brook Army Medical Center	Houston	Texas
United States	Digestive Associates	Las Vegas	Nevada
United States	Medical College of Virginia	Richmond	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
Manal Abdelmalek

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Analysis of MRI-PDFF Change From Baseline to Week 24 (Per Protocol Population)		Baseline to week 24
Primary	Analysis of MRI-PDFF Change From Baseline to Week 12 (Per Protocol Population)		Baseline to Week 12
Secondary	Analysis of ALT Change From Baseline to Week 24 (Per Protocol Population)		Baseline to week 24
Secondary	Analysis of ALT Change From Baseline to Week 12 (Per Protocol Population)		Baseline to week 12
Secondary	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
Secondary	Change in BMI (Body Mass Index)		Baseline, week 24
Secondary	Change in Hemoglobin A1C		Baseline, week 24
Secondary	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
Secondary	Percent Change in Cholesterol		Baseline, week 24
Secondary	Percent Change in Triglycerides		Baseline, week 24
Secondary	Percent Change in Low Density Lipoprotein (LDL) Cholesterol		Baseline, week 24
Secondary	Percent Change in High Density Lipoprotein (HDL)		Baseline, week 24
Secondary	Mean Serum Aspartate Aminotransferase (AST)		weeks 4, 8, 12, 16, 20, and 24
Secondary	Mean Serum Alanine Aminotransferase (ALT)		weeks 4, 8, 12, 16, 20, and 24
Secondary	Mean Serum Gamma-glutamyl Transpeptidase (GGT)		weeks 4, 8, 12, 16, 20, and 24
Secondary	Number of Subjects With ALT in Normal Range at Week 24	Normal range is <40 U/L	Week 24
Secondary	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
Secondary	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
Secondary	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
Secondary	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