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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
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| A | Active Comparator | JKB 121, 5 mg twice daily |
|
| B | Active Comparator | JKB 121, 10 mg twice daily |
|
| C | Placebo Comparator | Identical appearing placebo |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| JKB-121: 5 mg twice daily | Drug |
| ||
| JKB-121: 10 mg twice daily |
| Measure | Description | 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 |
| 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 | |
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Inclusion Criteria:
Exclusion Criteria:
Any chronic liver disease other than NASH
Cirrhosis, as assessed clinically or histologically
Presence of vascular liver disease
BMI ≤ 25 kg/m2
Excessive alcohol use (> 20 g/day) within the past 2 years
AST or ALT > 250 U/L.
Type 1 diabetes mellitus
Bariatric surgery in the past 5 years.
Weight gain of > 5% in past 6 months or > 10% change in past 12 months.
Contraindication to MRI
Inadequate venous access
HIV antibody positive, hepatitis B surface antigen positive (HBsAg), or Hepatitis C virus (HCV) RNA positive.
Receiving an elemental diet or parenteral nutrition
Chronic pancreatitis or pancreatic insufficiency
Any history of complications of cirrhosis
Concurrent conditions:
Concurrent medications which may treat NASH
HbA1C > 9.0%
Pregnancy or breastfeeding.
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| Name | Affiliation | Role |
|---|---|---|
| Manal F Abdelmalek, MD, MPH | Duke University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Digestive Disease Specialists of the Southeast | Dothan | Alabama | 36305 | United States | ||
| Northwestern University Feinberg School of Medicine |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36318027 | Derived | Nedrud MA, Chaudhry M, Middleton MS, Moylan CA, Lerebours R, Luo S, Farjat A, Guy C, Loomba R, Abdelmalek MF, Sirlin CB, Bashir MR. MRI Quantification of Placebo Effect in Nonalcoholic Steatohepatitis Clinical Trials. Radiology. 2023 Mar;306(3):e220743. doi: 10.1148/radiol.220743. Epub 2022 Nov 1. |
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| ID | Title | Description |
|---|---|---|
| FG000 | JKB 5 mg BID | JKB 121, 5 mg by mouth twice daily |
| FG001 | JKB 10 mg BID | JKB 121, 10 mg by mouth twice daily |
| FG002 | Placebo BID | Identical appearing placebo by mouth twice daily |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | JKB 5 mg BID | JKB 121, 5 mg twice daily |
| BG001 | JKB 10 mg BID | JKB 121, 10 mg twice daily |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Analysis of MRI-PDFF Change From Baseline to Week 24 (Per Protocol Population) | The per protocol population included only those patients with non-missing baseline (ie. screening) and the specified visit are included. If missing, the last valid measurement on or prior to the first date administration of study medication is used as baseline. | Posted | Least Squares Mean | 95% Confidence Interval | percentage of fat | Baseline to week 24 |
|
6 month
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | JKB 5 mg Twice Daily | JKB 121, 5 mg twice daily | 0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pancreatitis | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment | Deemed by PI and Sponsor not be attributable to study drug |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
This is a pilot study to assess safety and tolerability of JKB 121 in patients with biopsy-proven NASH. There The study was underpowered to detect rare events.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Manal F. Abdelmalek | Duke University | 919-684-8356 | manal.abdelmalek@duke.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Mar 2, 2016 | Aug 23, 2018 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Mar 31, 2017 | Oct 15, 2018 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D065626 | Non-alcoholic Fatty Liver Disease |
| ID | Term |
|---|---|
| D005234 | Fatty Liver |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
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|
| Placebo | Drug |
|
| 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 |
| Chicago |
| Illinois |
| 60611 |
| United States |
| Digestive Associates | Las Vegas | Nevada | 89102 | United States |
| Duke University | Durham | North Carolina | 27710 | United States |
| Digestive Disease Specialists | Cincinnati | Ohio | 45219 | United States |
| Brook Army Medical Center | Houston | Texas | 78234 | United States |
| University of Virginia Health Systems | Charlottesville | Virginia | 22903 | United States |
| Medical College of Virginia | Richmond | Virginia | 23298 | United States |
| BG002 |
| Placebo BID |
Identical appearing placebo |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Body Mass Index | Median | Standard Deviation | kg/m^2 |
|
| OG002 |
| Placebo |
Identical appearing placebo Placebo |
|
|
|
| Primary | Analysis of MRI-PDFF Change From Baseline to Week 12 (Per Protocol Population) | The per protocol population included only those patients with non-missing baseline (ie. screening) and the specified visit are included. If missing, the last valid measurement on or prior to the first date administration of study medication is used as baseline. | Posted | Least Squares Mean | 95% Confidence Interval | percentage | Baseline to Week 12 |
|
|
|
|
| Secondary | Analysis of ALT Change From Baseline to Week 24 (Per Protocol Population) | The per protocol population included only those patients with non-missing baseline (ie. screening) and the specified visit are included. If missing, the last valid measurement on or prior to the first date administration of study medication is used as baseline. | Posted | Least Squares Mean | 95% Confidence Interval | U/L | Baseline to week 24 |
|
|
|
|
| Secondary | Analysis of ALT Change From Baseline to Week 12 (Per Protocol Population) | The per protocol population included only those patients with non-missing baseline (ie. screening) and the specified visit are included. If missing, the last valid measurement on or prior to the first date administration of study medication is used as baseline. | Posted | Least Squares Mean | 95% Confidence Interval | U/L | 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. | No subjects reached remission; analysis not performed. | Posted | 24 weeks |
|
|
| Secondary | Change in BMI (Body Mass Index) | Only patients with non-missing baseline and the specified visit are included. | Posted | Least Squares Mean | 95% Confidence Interval | kg/m^2 | Baseline, week 24 |
|
|
|
| Secondary | Change in Hemoglobin A1C | Only patients with non-missing baseline and the specified visit are included | Posted | Least Squares Mean | 95% Confidence Interval | percentage of HbA1C | 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. | Only patients with non-missing baseline and the specified visit are included. | Posted | Least Squares Mean | 95% Confidence Interval | HOMA-IR index | Baseline, week 24 |
|
|
|
| Secondary | Percent Change in Cholesterol | Posted | Least Squares Mean | 95% Confidence Interval | percent change | Baseline, week 24 |
|
|
|
| Secondary | Percent Change in Triglycerides | Only patients with non-missing baseline and the specified visit are included. | Posted | Least Squares Mean | 95% Confidence Interval | percent change | Baseline, week 24 |
|
|
|
| Secondary | Percent Change in Low Density Lipoprotein (LDL) Cholesterol | Only patients with non-missing baseline and the specified visit are included. | Posted | Least Squares Mean | 95% Confidence Interval | percent change | Baseline, week 24 |
|
|
|
| Secondary | Percent Change in High Density Lipoprotein (HDL) | Only patients with non-missing baseline and the specified visit are included. | Posted | Least Squares Mean | 95% Confidence Interval | percent change | Baseline, week 24 |
|
|
|
| Secondary | Mean Serum Aspartate Aminotransferase (AST) | Number of subjects with a result at baseline and the specified visit. Baseline is defined as the measurement at Day 1. | Posted | Mean | Standard Deviation | U/L | weeks 4, 8, 12, 16, 20, and 24 |
|
|
|
| Secondary | Mean Serum Alanine Aminotransferase (ALT) | Number of subjects with a result at baseline and the specified visit. Baseline is defined as the measurement at Day 1. | Posted | Mean | Standard Deviation | U/L | weeks 4, 8, 12, 16, 20, and 24 |
|
|
|
| Secondary | Mean Serum Gamma-glutamyl Transpeptidase (GGT) | Number of subjects with a result at baseline and the specified visit. Baseline is defined as the measurement at Day 1. | Posted | Mean | Standard Deviation | U/L | 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 | Number of subjects with an ALT result at the specified visit | Posted | Count of Participants | Participants | Week 24 |
|
|
|
| Secondary | Maximum Observed Concentrations (Cmax) | PK Substudy Population | Posted | Mean | Standard Deviation | ng/mL | 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) | PK Substudy Population | Posted | Mean | Standard Deviation | ng/mL | 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) | PK Substudy Population | Posted | Mean | Standard Deviation | h*ng/mL | 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 | PK Substudy Population | Posted | Mean | Standard Deviation | h | 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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|
| 21 |
| 1 |
| 21 |
| 18 |
| 21 |
| EG001 | Placebo Twice Daily | Placebo, twice daily | 0 | 22 | 0 | 22 | 15 | 22 |
| EG002 | JKB 121 10 mg Twice Daily | JKB 121, 10 mg twice daily | 0 | 22 | 1 | 22 | 19 | 22 |
|
| Acute on Chronic Hypoxemic Respiratory Failure | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment | Deemed not attributable to study drub |
|
| Diarrhea | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA (10.0) | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA (10.0) | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA (10.0) | Systematic Assessment |
|
| Abnormal dreams | Psychiatric disorders | MedDRA (10.0) | Systematic Assessment |
|
| Oralpharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| Pruritis | Skin and subcutaneous tissue disorders | MedDRA (10.0) | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| Nasal Congetion | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| Injury | Injury, poisoning and procedural complications | MedDRA (10.0) | Systematic Assessment |
|
| Urinary Tract Infection | Renal and urinary disorders | MedDRA (10.0) | Systematic Assessment |
|
| Nasopharynitis | Reproductive system and breast disorders | MedDRA (10.0) | Systematic Assessment |
|
| Upper respiratory tract infection | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
|
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| ANCOVA |
The change from baseline as the dependent variable, baseline value as a covariate, and treatment group and diabetes stratum as factors. |
| 0.4968 |
The p-value is not adjusted for multiple comparisons. The threshold for statistical significance was <0.05. |
| Other |
| ANCOVA |
Change from baseline as the dependent variable, baseline value as a covariate, and treatment group and diabetes stratum as factors. |
| 0.1806 |
The p-value is not adjusted for multiple comparisons. The threshold for statistical significance was <0.05. |
| Other |
| ANCOVA |
The change from baseline as the dependent variable, baseline value as a covariate, and treatment group and diabetes stratum as factors. |
| 0.2530 |
The p-value is not adjusted for multiple comparisons. The threshold for statistical significance was <0.05. |
| Other |
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| time 0 to 12 hours |
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