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JKB-121 for the Treatment of Nonalcoholic Steatohepatitis

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ClinicalTrials.gov Identifier: NCT02442687
Recruitment Status : Completed
First Posted : May 13, 2015
Results First Posted : January 7, 2019
Last Update Posted : January 7, 2019
Sponsor:
Information provided by (Responsible Party):
Manal Abdelmalek, Duke University

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

Condition or disease Intervention/treatment Phase
Nonalcoholic Steatohepatitis Drug: JKB-121: 5 mg twice daily Drug: JKB-121: 10 mg twice daily Drug: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 65 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Placebo Controlled, Parallel-Group, Phase II Trial of JKB-121 for the Treatment of Nonalcoholic Steatohepatitis (NASH)
Actual Study Start Date : August 1, 2015
Actual Primary Completion Date : September 24, 2017
Actual Study Completion Date : September 24, 2017


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



Primary Outcome Measures :
  1. Analysis of MRI-PDFF Change From Baseline to Week 24 (Per Protocol Population) [ Time Frame: Baseline to week 24 ]
  2. Analysis of MRI-PDFF Change From Baseline to Week 12 (Per Protocol Population) [ Time Frame: Baseline to Week 12 ]

Secondary Outcome Measures :
  1. Analysis of ALT Change From Baseline to Week 24 (Per Protocol Population) [ Time Frame: Baseline to week 24 ]
  2. Analysis of ALT Change From Baseline to Week 12 (Per Protocol Population) [ Time Frame: Baseline to week 12 ]
  3. Time to Remission (in Weeks) [ Time Frame: 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.

  4. Change in BMI (Body Mass Index) [ Time Frame: Baseline, week 24 ]
  5. Change in Hemoglobin A1C [ Time Frame: Baseline, week 24 ]
  6. Change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) [ Time Frame: 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.

  7. Percent Change in Cholesterol [ Time Frame: Baseline, week 24 ]
  8. Percent Change in Triglycerides [ Time Frame: Baseline, week 24 ]
  9. Percent Change in Low Density Lipoprotein (LDL) Cholesterol [ Time Frame: Baseline, week 24 ]
  10. Percent Change in High Density Lipoprotein (HDL) [ Time Frame: Baseline, week 24 ]
  11. Mean Serum Aspartate Aminotransferase (AST) [ Time Frame: weeks 4, 8, 12, 16, 20, and 24 ]
  12. Mean Serum Alanine Aminotransferase (ALT) [ Time Frame: weeks 4, 8, 12, 16, 20, and 24 ]
  13. Mean Serum Gamma-glutamyl Transpeptidase (GGT) [ Time Frame: weeks 4, 8, 12, 16, 20, and 24 ]
  14. Number of Subjects With ALT in Normal Range at Week 24 [ Time Frame: Week 24 ]
    Normal range is <40 U/L

  15. Maximum Observed Concentrations (Cmax) [ Time Frame: 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 ]
  16. Minimum Observed Concentration (Cmin) [ Time Frame: 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 ]
  17. Area Under Concentration-time (AUC) [ Time Frame: 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 ]
  18. Half-life [ Time Frame: 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 ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02442687


Locations
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United States, Alabama
Digestive Disease Specialists of the Southeast
Dothan, Alabama, United States, 36305
United States, Illinois
Northwestern University Feinberg School of Medicine
Chicago, Illinois, United States, 60611
United States, Nevada
Digestive Associates
Las Vegas, Nevada, United States, 89102
United States, North Carolina
Duke University
Durham, North Carolina, United States, 27710
United States, Ohio
Digestive Disease Specialists
Cincinnati, Ohio, United States, 45219
United States, Texas
Brook Army Medical Center
Houston, Texas, United States, 78234
United States, Virginia
University of Virginia Health Systems
Charlottesville, Virginia, United States, 22903
Medical College of Virginia
Richmond, Virginia, United States, 23298
Sponsors and Collaborators
Manal Abdelmalek
Investigators
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Principal Investigator: Manal F Abdelmalek, MD, MPH Duke University
  Study Documents (Full-Text)

Documents provided by Manal Abdelmalek, Duke University:
Study Protocol  [PDF] March 2, 2016
Statistical Analysis Plan  [PDF] March 31, 2017


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Responsible Party: Manal Abdelmalek, Associate Professor, Duke University
ClinicalTrials.gov Identifier: NCT02442687     History of Changes
Other Study ID Numbers: Pro00062677
First Posted: May 13, 2015    Key Record Dates
Results First Posted: January 7, 2019
Last Update Posted: January 7, 2019
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Fatty Liver
Non-alcoholic Fatty Liver Disease
Liver Diseases
Digestive System Diseases