Obese Patients With Non-alcoholic Steatohepatitis (NASH)
Conditions
Keywords
non-alcoholic steatohepatitis, NASH, Obese, Type 2 diabetes mellitus, non-alcoholic fatty liver disease
Brief summary
The purpose of this study was to assess the effects of LIK066 on a variety of metabolic and inflammation biomarkers in patients with non-alcoholic steatohepatitis (NASH)
Detailed description
This was a a non-confirmatory, multicenter, patient and investigator blinded, randomized, placebo-controlled, parallel group study in patients with non-alcoholic steatohepatitis (NASH). The study consisted of a 28 day screening period (Day -44 to Day -16), a baseline period of 14 days (Day -15 to Day -1), a treatment period of 12 weeks (Day 1 to Day 84), and a study completion evaluation approximately 28 days after the last drug administration. The patients were advised to maintain their recommended diet during the study. Patients who met the inclusion/exclusion criteria at screening went to the study site for baseline assessments. All baseline safety evaluation results were available prior to the first dosing. The study started by enrolling patients into the 150 mg and placebo arms with a randomization ratio of 2:1. After the enrollment of the first 33 patients, the 30 mg arm was added to the study and the randomization ratio changed to a 2:4:1 ratio (150 mg: 30 mg: placebo) to maintain the 2:2:1 ratio across the three groups (150 mg: 30 mg: placebo) at study completion.
Interventions
DRUGLIK066
Film coated tablet of LIK066 either 30mg or 150 mg was mostly administered once daily before lunch, except on Day 56 when it was administered before breakfast and in fasted state on Day 84
DRUGPlacebo
LIK066 0 mg film-coated tablet(Placebo matching tablets) was mostly administered once daily before lunch, except on Day 56 when it was administered before breakfast and in fasted state on Day 84.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
EITHER -Histologic confirmed NASH based on liver biopsy obtained 2 years or less before randomization with a fibrosis level of F1, F2 or F3 in the absence of a histological diagnosis of alternative chronic liver disease AND ALT greater than or equal to 50 IU/L (males) or greater than or equal to 35 IU/L (females) at screening. OR Phenotypic diagnosis of NASH based on presence of ALL three of the following at screening: * ALT greater than or equal to 50IU/L (males) or greater than or equal to 35 IU/L (females) AND * BMI greater than or equal to 27 kg/m\^2 (in patients with a self-identified race other than Asian) or greater than or equal to 23 kg/m\^2 (in patients with a self identified Asian race) AND * Diagnosis of Type 2 diabetes mellitus by HbA1c: greater than or equal to 6.5 % and less than or equal to 10% * Patients must weigh no more than 150 kg (330 lbs) to participate in the study. * Male and female patients 18 years or older at the time of screening visit.
Exclusion criteria
* History or presence of other concomitant liver diseases * History or current diagnosis of ECG abnormalities * Use of GLP-1 agonists, SGLT2 inhibitors, TZDs, FXR agonists and any pharmacologically active weight loss drugs within 6 weeks of screening and until end of study * Patients with contraindications to MRI imaging * Current or history of significant alcohol consumption * Clinical evidence of hepatic decompensation or severe liver impairment * Women of child bearing potential (unless on basic contraception methods) * Presence of liver cirrhosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Alanine Aminotransferase (ALT) at Week 12 | Baseline, Week 12 | Alanine aminotransferase (ALT) is an enzyme found primarily in the liver. ALT is increased with liver damage. In this study, the blood levels of ALT was used to detect liver injury. Baseline is defined as the mean of measurements taken at the Screening and Baseline visits. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Total Body Weight at Week 12 | Baseline, Week 12 | Body weight (to the nearest 0.1 kilogram \[kg\] was measured on a calibrated scale. The measurement was performed with the study subject in underwear and without shoes; or while wearing minimal indoor clothing. |
| Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score at Week 12 | Baseline, Week 12 | The markers of fibrosis assessed in this test comprised hyaluronic acid (HA), tissue inhibitor of metalloproteinase (TIMP1) and procollagen III N-terminal peptide (PIIINP); these are components of the extracellular matrix and basement sinusoidal membrane of the liver and are elevated during fibrogenesis as a result of activation of the hepatic stellate cell. The ELF test is a composite score: \< 7.7: no to mild fibrosis; ≥ 7.7 - \< 9.8: Moderate fibrosis; ≥ 9.8 - \< 11.3: Severe fibrosis; ≥ 11.3: Cirrhosis. A negative change from Baseline indicates decreased fibrosis. |
| Change From Baseline in the Concentration of Hyaluronic Acid at Week 12. | Baseline, Week 12 | Hyaluronic Acid is a non-invasive marker of liver fibrosis. It was accessed by Enhanced liver fibrosis Test (ELF). |
| Change From Baseline in the Concentration of Procollagen Type Iii N-Terminal Peptide (PIIINP) at Week 12. | Baseline, Week 12 | PIIINP is a non-invasive marker of liver fibrosis. It was accessed by Enhanced liver fibrosis Test (ELF). |
| Change From Baseline in Percent Liver Fat at Week 12 | Baseline, Week 12 | Percent (%) Liver fat was measured by Magnetic Resonance Imaging Proton Density Liver Fat Fraction(MRIPDFF). Patients underwent magnetic resonance imaging twice during the course of the study ( baseline and end of treatment) to quantitate liver fat. |
| Pharmacokinetics of LIK066: Observed Maximum Plasma Concentration (Cmax) Following Drug Administration | Day 56 (pre-dose and 1, 2, 4 and 6 hours post-dose) | Cmax is the observed maximum plasma concentration following drug administration (ng/mL) |
| Pharmacokinetics of LIK066: Observed Maximum Time Duration of Maximum Concentration (Tmax) Following Drug Administration | Day 56 (pre-dose and 1, 2, 4 and 6 hours post-dose) | Tmax is the time to reach the maximum concentration after drug administration (hour). The time points presented are the actual and not the planned time points. |
| Pharmacokinetics of LIK066: Observed Area Under the Curve up to the Last Measurable Concentration (AUClast) Following Drug Administration | Day 56 (pre-dose and 1, 2, 4 and 6 hours post-dose) | AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (hour\*ng/mL) |
| Change From Baseline in Aspartate Aminotransferase (AST) at Week 12 | Baseline, Week 12 | Aspartate aminotransferase (AST) is an enzyme found in many cells of the body specifically those of the liver, heart and skeletal muscle. In healthy individuals, levels of AST in the blood are low. When liver or muscle cells are injured, they release AST into the blood. In this study, the blood levels of AST was used to detect liver injury. Baseline is defined as the mean of measurements taken at the Screening and Baseline visits. |
| Change From Baseline in the Concentration of Tissue Inhibitor Of Metalloproteinase 1 (TIMP-1) at Week 12. | Baseline, Week 12 | TIMP-1 is a non-invasive marker of liver fibrosis. It was accessed by Enhanced liver fibrosis Test (ELF). |
Countries
Argentina, Canada, Israel, Netherlands, Russia, Taiwan, Thailand, United States
Participant flow
Recruitment details
A total of 107 participants were enrolled in 15 centers across 8 countries: Argentina (2), Canada (1), Israel (3), Netherlands (1), Russia federation (1), Taiwan (2), Thailand (1), United States (4).
Pre-assignment details
Participants were randomized in 2:2:1 ratio to the 3 groups: LIK066 150 mg, LIK066 30 mg and placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo LIK066 0 mg film-coated tablet(Placebo matching tablets) was mostly administered once daily before lunch, except on Day 56 when it was administered before breakfast and in fasted state on Day 84. | 21 |
| LIK066 30 mg Film coated tablet of LIK066 30 mg was mostly administered once daily before lunch, except on Day 56 when it was administered before breakfast and in fasted state on Day 84. | 43 |
| LIK066 150 mg Film coated tablet of LIK066 150 mg was mostly administered once daily before lunch, except on Day 56 when it was administered before breakfast and in fasted state on Day 84. | 43 |
| Total | 107 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Patient/guardian decision | 0 | 3 | 0 |
| Overall Study | Protocol deviation | 1 | 3 | 0 |
Baseline characteristics
| Characteristic | Placebo | LIK066 30 mg | LIK066 150 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 48.0 years STANDARD_DEVIATION 11.16 | 53.1 years STANDARD_DEVIATION 12.57 | 49.5 years STANDARD_DEVIATION 11.1 | 50.7 years STANDARD_DEVIATION 11.8 |
| Race/Ethnicity, Customized Asian | 3 Participants | 8 Participants | 4 Participants | 15 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 17 Participants | 34 Participants | 35 Participants | 86 Participants |
| Sex: Female, Male Female | 12 Participants | 25 Participants | 22 Participants | 59 Participants |
| Sex: Female, Male Male | 9 Participants | 18 Participants | 21 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 43 | 0 / 43 | 0 / 21 | 0 / 107 |
| other Total, other adverse events | 31 / 43 | 36 / 43 | 18 / 21 | 85 / 107 |
| serious Total, serious adverse events | 0 / 43 | 0 / 43 | 1 / 21 | 1 / 107 |
Outcome results
Primary
Change From Baseline in Alanine Aminotransferase (ALT) at Week 12
Alanine aminotransferase (ALT) is an enzyme found primarily in the liver. ALT is increased with liver damage. In this study, the blood levels of ALT was used to detect liver injury. Baseline is defined as the mean of measurements taken at the Screening and Baseline visits.
Time frame: Baseline, Week 12
Population: Pharmacodynamics (PD) analysis set: included all participants with available PD data, who received any study drug and had valid measurements for the outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LIK066 30 mg | Change From Baseline in Alanine Aminotransferase (ALT) at Week 12 | -22.06 Units per Liter (U/L) | Standard Error 4.16 |
| LIK066 150 mg | Change From Baseline in Alanine Aminotransferase (ALT) at Week 12 | -30.41 Units per Liter (U/L) | Standard Error 4.52 |
| Placebo | Change From Baseline in Alanine Aminotransferase (ALT) at Week 12 | -8.77 Units per Liter (U/L) | Standard Error 5.99 |
p-value: 0.00580% CI: [-31.33, -11.94]ANCOVA
p-value: 0.07580% CI: [-22.8, -3.78]ANCOVA
p-value: 0.17880% CI: [0.41, 16.29]ANCOVA
Secondary
Change From Baseline in Aspartate Aminotransferase (AST) at Week 12
Aspartate aminotransferase (AST) is an enzyme found in many cells of the body specifically those of the liver, heart and skeletal muscle. In healthy individuals, levels of AST in the blood are low. When liver or muscle cells are injured, they release AST into the blood. In this study, the blood levels of AST was used to detect liver injury. Baseline is defined as the mean of measurements taken at the Screening and Baseline visits.
Time frame: Baseline, Week 12
Population: Pharmacodynamics (PD) analysis set: included all participants with available PD data, who received any study drug and had valid measurements for the outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LIK066 30 mg | Change From Baseline in Aspartate Aminotransferase (AST) at Week 12 | -13.45 Units per liter (U/L) | Standard Error 2.46 |
| LIK066 150 mg | Change From Baseline in Aspartate Aminotransferase (AST) at Week 12 | -17.01 Units per liter (U/L) | Standard Error 2.68 |
| Placebo | Change From Baseline in Aspartate Aminotransferase (AST) at Week 12 | -2.30 Units per liter (U/L) | Standard Error 3.54 |
p-value: 0.01380% CI: [-16.79, -5.5]ANCOVA
p-value: 0.00180% CI: [-20.43, -8.98]ANCOVA
p-value: 0.33280% CI: [-1.15, 8.28]ANCOVA
Secondary
Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score at Week 12
The markers of fibrosis assessed in this test comprised hyaluronic acid (HA), tissue inhibitor of metalloproteinase (TIMP1) and procollagen III N-terminal peptide (PIIINP); these are components of the extracellular matrix and basement sinusoidal membrane of the liver and are elevated during fibrogenesis as a result of activation of the hepatic stellate cell. The ELF test is a composite score: \< 7.7: no to mild fibrosis; ≥ 7.7 - \< 9.8: Moderate fibrosis; ≥ 9.8 - \< 11.3: Severe fibrosis; ≥ 11.3: Cirrhosis. A negative change from Baseline indicates decreased fibrosis.
Time frame: Baseline, Week 12
Population: Pharmacodynamics (PD) analysis set: included all participants with available PD data, who received any study drug and had valid measurements for the outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LIK066 30 mg | Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score at Week 12 | -0.2 scores on a scale | Standard Deviation 0.65 |
| LIK066 150 mg | Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score at Week 12 | -0.1 scores on a scale | Standard Deviation 0.61 |
| Placebo | Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score at Week 12 | 0.1 scores on a scale | Standard Deviation 0.37 |
Secondary
Change From Baseline in Percent Liver Fat at Week 12
Percent (%) Liver fat was measured by Magnetic Resonance Imaging Proton Density Liver Fat Fraction(MRIPDFF). Patients underwent magnetic resonance imaging twice during the course of the study ( baseline and end of treatment) to quantitate liver fat.
Time frame: Baseline, Week 12
Population: Pharmacodynamics (PD) analysis set: included all participants with available PD data, who received any study drug and had valid measurements for the outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LIK066 30 mg | Change From Baseline in Percent Liver Fat at Week 12 | -4.40 Percentage of Liver Fat | Standard Error 0.81 |
| LIK066 150 mg | Change From Baseline in Percent Liver Fat at Week 12 | -6.92 Percentage of Liver Fat | Standard Error 0.87 |
| Placebo | Change From Baseline in Percent Liver Fat at Week 12 | -2.67 Percentage of Liver Fat | Standard Error 1.17 |
p-value: 0.23580% CI: [-3.6, 0.14]ANCOVA
p-value: 0.00480% CI: [-6.14, -2.37]ANCOVA
p-value: 0.03780% CI: [0.98, 4.07]ANCOVA
Secondary
Change From Baseline in the Concentration of Hyaluronic Acid at Week 12.
Hyaluronic Acid is a non-invasive marker of liver fibrosis. It was accessed by Enhanced liver fibrosis Test (ELF).
Time frame: Baseline, Week 12
Population: Pharmacodynamics (PD) analysis set: included all participants with available PD data, who received any study drug and had valid measurements for the outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LIK066 30 mg | Change From Baseline in the Concentration of Hyaluronic Acid at Week 12. | -3.4 ug/L | Standard Deviation 75.38 |
| LIK066 150 mg | Change From Baseline in the Concentration of Hyaluronic Acid at Week 12. | 0.4 ug/L | Standard Deviation 30.56 |
| Placebo | Change From Baseline in the Concentration of Hyaluronic Acid at Week 12. | 4.7 ug/L | Standard Deviation 21.73 |
Secondary
Change From Baseline in the Concentration of Procollagen Type Iii N-Terminal Peptide (PIIINP) at Week 12.
PIIINP is a non-invasive marker of liver fibrosis. It was accessed by Enhanced liver fibrosis Test (ELF).
Time frame: Baseline, Week 12
Population: Pharmacodynamics (PD) analysis set: included all participants with available PD data, who received any study drug and had valid measurements for the outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LIK066 30 mg | Change From Baseline in the Concentration of Procollagen Type Iii N-Terminal Peptide (PIIINP) at Week 12. | -1.7 ug/L | Standard Deviation 2.73 |
| LIK066 150 mg | Change From Baseline in the Concentration of Procollagen Type Iii N-Terminal Peptide (PIIINP) at Week 12. | -1.2 ug/L | Standard Deviation 3.66 |
| Placebo | Change From Baseline in the Concentration of Procollagen Type Iii N-Terminal Peptide (PIIINP) at Week 12. | 0.3 ug/L | Standard Deviation 1.88 |
Secondary
Change From Baseline in the Concentration of Tissue Inhibitor Of Metalloproteinase 1 (TIMP-1) at Week 12.
TIMP-1 is a non-invasive marker of liver fibrosis. It was accessed by Enhanced liver fibrosis Test (ELF).
Time frame: Baseline, Week 12
Population: Pharmacodynamics (PD) analysis set: included all participants with available PD data, who received any study drug and had valid measurements for the outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LIK066 30 mg | Change From Baseline in the Concentration of Tissue Inhibitor Of Metalloproteinase 1 (TIMP-1) at Week 12. | -3.0 ug/L | Standard Deviation 38.98 |
| LIK066 150 mg | Change From Baseline in the Concentration of Tissue Inhibitor Of Metalloproteinase 1 (TIMP-1) at Week 12. | -10.9 ug/L | Standard Deviation 38.21 |
| Placebo | Change From Baseline in the Concentration of Tissue Inhibitor Of Metalloproteinase 1 (TIMP-1) at Week 12. | 10.3 ug/L | Standard Deviation 25.73 |
Secondary
Percent Change From Baseline in Total Body Weight at Week 12
Body weight (to the nearest 0.1 kilogram \[kg\] was measured on a calibrated scale. The measurement was performed with the study subject in underwear and without shoes; or while wearing minimal indoor clothing.
Time frame: Baseline, Week 12
Population: Pharmacodynamics (PD) analysis set: included all participants with available PD data, who received any study drug and had valid measurements for the outcome measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LIK066 30 mg | Percent Change From Baseline in Total Body Weight at Week 12 | -3.48 percentage change | Standard Error 0.47 |
| LIK066 150 mg | Percent Change From Baseline in Total Body Weight at Week 12 | -4.51 percentage change | Standard Error 0.52 |
| Placebo | Percent Change From Baseline in Total Body Weight at Week 12 | -0.33 percentage change | Standard Error 0.68 |
p-value: <0.00180% CI: [-4.22, -2.08]ANCOVA
p-value: <0.00180% CI: [-5.28, -3.08]ANCOVA
p-value: 0.14880% CI: [0.12, 1.94]ANCOVA
Secondary
Pharmacokinetics of LIK066: Observed Area Under the Curve up to the Last Measurable Concentration (AUClast) Following Drug Administration
AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (hour\*ng/mL)
Time frame: Day 56 (pre-dose and 1, 2, 4 and 6 hours post-dose)
Population: Pharmacokinetics (PK) analysis set consisted of LIK066 treated patients. Placebo patients were excluded from the PK analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LIK066 30 mg | Pharmacokinetics of LIK066: Observed Area Under the Curve up to the Last Measurable Concentration (AUClast) Following Drug Administration | 1280 hour*ng/mL | Standard Deviation 413 |
| LIK066 150 mg | Pharmacokinetics of LIK066: Observed Area Under the Curve up to the Last Measurable Concentration (AUClast) Following Drug Administration | 5770 hour*ng/mL | Standard Deviation 1680 |
Secondary
Pharmacokinetics of LIK066: Observed Maximum Plasma Concentration (Cmax) Following Drug Administration
Cmax is the observed maximum plasma concentration following drug administration (ng/mL)
Time frame: Day 56 (pre-dose and 1, 2, 4 and 6 hours post-dose)
Population: Pharmacokinetics (PK) analysis set consisted of LIK066 treated patients. Placebo patients were excluded from the PK analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LIK066 30 mg | Pharmacokinetics of LIK066: Observed Maximum Plasma Concentration (Cmax) Following Drug Administration | 405 ng/mL | Standard Deviation 109 |
| LIK066 150 mg | Pharmacokinetics of LIK066: Observed Maximum Plasma Concentration (Cmax) Following Drug Administration | 1810 ng/mL | Standard Deviation 729 |
Secondary
Pharmacokinetics of LIK066: Observed Maximum Time Duration of Maximum Concentration (Tmax) Following Drug Administration
Tmax is the time to reach the maximum concentration after drug administration (hour). The time points presented are the actual and not the planned time points.
Time frame: Day 56 (pre-dose and 1, 2, 4 and 6 hours post-dose)
Population: Pharmacokinetics (PK) analysis set consisted of LIK066 treated patients. Placebo patients were excluded from the PK analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LIK066 30 mg | Pharmacokinetics of LIK066: Observed Maximum Time Duration of Maximum Concentration (Tmax) Following Drug Administration | 1.00 hours |
| LIK066 150 mg | Pharmacokinetics of LIK066: Observed Maximum Time Duration of Maximum Concentration (Tmax) Following Drug Administration | 1.51 hours |