Non-alcoholic Fatty Liver Disease (NAFLD)
Conditions
Keywords
Multi-center,, randomized,, double-blind,, NAFLD,, elevated triglycerides
Brief summary
The purpose of this study was to determine whether LCQ908 effectively lowers liver fat, as assessed by MRI and to assess its safety and tolerability profile in subjects with non-alcoholic fatty liver disease (NAFLD).
Interventions
DRUGLCQ908
LCQ908 5 mg, 10 mg, 20 mg tablets
DRUGplacebo
Matching placebo of LCQ908 5 mg, 10 mg, 20 mg tablets.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
* History of liver steatosis during the preceding 24 months * History of fasting TGs \> 200 mg/dL (confirmed at screening). * Liver fat ≥ 10% as determined by the central MRI laboratory. * Subjects on the following medications can be included if these medications are medically necessary, cannot be stopped and the investigator feels their dose will remain stable for the duration of the double-blind treatment period: 1. Stable dose of anti-diabetic medications (metformin and/or sulfonylureas) for at least 8 weeks prior to screening. 2. Stable doses of beta-blockers and thiazide diuretics for at least 8 weeks prior to screening. 3. Stable doses of fibrates, statins, niacin, ezetimibe for at least 8 weeks prior to screening. 4. Stable dose of vitamin E in patients taking \>200 IU/day for at least 6 months prior to screening.
Exclusion criteria
* Treatment with omega-3-acid ethyl esters or omega-3-polyunsaturated fatty acid (PUFA)-containing supplements \> 200 mg per day within 8 weeks of screening. * Treatment with antiretrovirals, tamoxifen, methotrexate, cyclophosphamide, isotretinoin, bile acid binding resins or pharmacologic doses of oral glucocorticoids (≥10 mg of prednisone per day or equivalent) within 8 weeks of screening. * ALT or AST \> 250 IU/L at the time of screening. * History/current evidence of heavy alcohol use or alcoholism (\> 21 drinks per week in men and \> 14 drinks per week in women) over a 2-year period prior to screening. * Presence of chronic liver disease, such as chronic hepatitis B and/or C, alcoholic liver disease, hemochromatosis, Wilson's disease, known cirrhosis. * Platelet count \<150,000 at screening. * BMI \>45 Kg/m2. Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Percentage of Fat in the Liver as Assessed Using MRI at Week 24 | From baseline to week 24 | Patients were to undergo MRI three times during the course of the study to assess liver fat. Baseline is defined as the value collected at Week -2 MRI assessment (approximately between Day -7 to -14). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Responders at Week 12 | At week 12 | The response criteria are defined as: a. A reduction of ≥ 30% from baseline in liver fat b. A reduction of ≥ 50% from baseline in liver fat c. Liver fat content \< 10% d. Liver fat content \< 5.6%. Percentage is calculated as (m/n)\*100 where m: number of patients who are responders. n: number of patients with non-missing percent liver fat at that visit. |
| Percentage of Responders at Week 24 | From baseline to week 24 | The response criteria are defined as: a. A reduction of ≥ 30% from baseline in liver fat b. A reduction of ≥ 50% from baseline in liver fat c. Liver fat content \< 10% d. Liver fat content \< 5.6%. Percentage is calculated as (m/n)\*100 where m: number of patients who are responders. n: number of patients with non-missing percent liver fat at that visit. |
| Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 6 | From Baseline to week 6 | Change from baseline ALT, AST and GGT values collected post-dose was analyzed using Mixed Model of Repeated Measurements (MMRM). Baseline is defined as the value collected at Week 0 (randomization). Treatment group and visit were fitted as factors and baseline was fitted as a continuous covariate. |
| Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 12 | From Baseline to week 12 | Change from baseline ALT, AST and GGT values collected post-dose was analyzed using Mixed Model of Repeated Measurements (MMRM). Baseline is defined as the value collected at Week 0 (randomization). Treatment group and visit were fitted as factors and baseline was fitted as a continuous covariate. |
| Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 24 | From Baseline to week 24 | Change from baseline ALT, AST and GGT values collected post-dose was analyzed using Mixed Model of Repeated Measurements (MMRM). Baseline is defined as the value collected at Week 0 (randomization). Treatment group and visit were fitted as factors and baseline was fitted as a continuous covariate. |
| Change From Baseline in Percentage of Fat in the Liver as Assessed Using MRI at Week 12 | From baseline to week 12 | Patients were to undergo MRI three times during the course of the study to assess liver fat. Baseline is defined as the value collected at Week -2 MRI assessment (approximately between Day -7 to -14). |
| Percent Change From Baseline in Fasting Triglycerides | Baseline, 6, 12 and 24 weeks | Blood samples were collected for a fasting triglycerides (TG) after a 10-hour (overnight) fast. Adjusted geometric means which is reported are calculated by back-transforming the adjusted means from the model and expressing as a percentage change from baseline. Baseline is defined as the value collected at Week 0 (randomization). |
| Post-prandial Peak Triglycerides Over 0 - 8 Hours | Baseline, 6 and 24 weeks | Post-prandial peak triglycerides is reported as maximum triglyceride value over 0-8 hours. Adjusted geometric means which is reported are calculated by back-transforming the adjusted means from the model. Baseline is defined as the value collected at Week 0 (randomization). |
| Change From Baseline in Body Weight | Baseline, 12 and 24 weeks | — |
| Change From Baseline in Waist Circumference | Baseline, 12 and 24 weeks | — |
| Number of Patients With Adverse Events, Serious Adverse Events (SAEs) and Death as Assessment of Safety and Tolerability | 24 weeks | — |
| Percentage of Patients With Normalized Liver Enzymes | Baseline, week 6, week 12 and week 24 | Normalized liver enzymes defined as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 40 U/L. Normal/High categories at baseline are defined by criteria of normal. Better is defined as high' at baseline and 'normal' post-dose; Same is defined as 'normal' at baseline and 'normal' post-dose or 'high' at baseline and 'high' post-dose; Worse is defined as 'normal' at baseline and 'high' post-dose. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients randomized to Placebo arm, received matching placebo to 5 mg, 10 mg and 20 mg pradigstat (LCQ908) once daily for 24 weeks. Each patient was to receive 3 tablets a day. All patients were required to remain on their American Heart Association (AHA) diet for the entire duration of the study. | 20 |
| Pradigastat (LCQ908) 5mg/10mg Patients, randomized to pradigastat 5/10 mg, initially began with pradigastat (LCQ908) 5 mg once daily and then were up-titrated, if pradigastat (LCQ908) 5 mg once daily was tolerated, to pradigastat 10 mg once daily at Week 2. Total treatment duration was 24 weeks. Each patient was to receive 3 tablets a day. All patients were required to remain on their American Heart Association (AHA) diet for the entire duration of the study. | 11 |
| Pradigastat (LCQ908) 10mg/20mg Patients, randomized to pradigastat 10/20 mg, initially began with pradigastat (LCQ908) 10 mg once daily and then were up-titrated, if pradigastat (LCQ908) 10 mg once daily was tolerated, to pradigastat 20 mg once daily at Week 2. Total treatment duration was 24 weeks. Each patient was to receive 3 tablets a day. All patients were required to remain on their American Heart Association (AHA) diet for the entire duration of the study. | 21 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 4 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Subject/guardian decision | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Pradigastat (LCQ908) 5mg/10mg | Pradigastat (LCQ908) 10mg/20mg | Total |
|---|---|---|---|---|
| Age, Continuous | 55.9 Years STANDARD_DEVIATION 7.69 | 58.7 Years STANDARD_DEVIATION 6.56 | 47.7 Years STANDARD_DEVIATION 11.76 | 53.2 Years STANDARD_DEVIATION 10.32 |
| Sex: Female, Male Female | 10 Participants | 6 Participants | 10 Participants | 26 Participants |
| Sex: Female, Male Male | 10 Participants | 5 Participants | 11 Participants | 26 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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 14 / 20 | 9 / 11 | 20 / 21 | 29 / 32 |
| serious Total, serious adverse events | 3 / 20 | 1 / 11 | 2 / 21 | 3 / 32 |
Outcome results
Primary
Change From Baseline in Percentage of Fat in the Liver as Assessed Using MRI at Week 24
Patients were to undergo MRI three times during the course of the study to assess liver fat. Baseline is defined as the value collected at Week -2 MRI assessment (approximately between Day -7 to -14).
Time frame: From baseline to week 24
Population: Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with baseline and post-baseline value at week 24 are included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Percentage of Fat in the Liver as Assessed Using MRI at Week 24 | 0.00 Percentage of liver fat |
| Pradigastat (LCQ908) 5mg/10mg | Change From Baseline in Percentage of Fat in the Liver as Assessed Using MRI at Week 24 | -1.68 Percentage of liver fat |
| Pradigastat (LCQ908) 10mg/20mg | Change From Baseline in Percentage of Fat in the Liver as Assessed Using MRI at Week 24 | -2.89 Percentage of liver fat |
Comparison: Hypothesis was tested at the 1-sided 5% significance level to assess if LCQ908 5mg/10mg was different from placebo.p-value: 0.312890% CI: [-4.46, 1.09]Mixed Model of Repeated Measurements
Comparison: Hypothesis was tested at the 1-sided 5% significance level to assess if LCQ908 10mg/20mg was different from placebo.p-value: 0.045790% CI: [-5.25, -0.53]Mixed Model of Repeated Measurements
Secondary
Change From Baseline in Body Weight
Time frame: Baseline, 12 and 24 weeks
Population: Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with both baseline and post-baseline values at different timepoints were included in this endpoint analysis
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | Change From Baseline in Body Weight | Change from baseline to week 12 (n=20, 11, 17) | -1.3 kilogram (kg) |
| Placebo | Change From Baseline in Body Weight | Change from baseline to week 24 (n=18, 11, 17) | -1.1 kilogram (kg) |
| Pradigastat (LCQ908) 5mg/10mg | Change From Baseline in Body Weight | Change from baseline to week 12 (n=20, 11, 17) | -2.2 kilogram (kg) |
| Pradigastat (LCQ908) 5mg/10mg | Change From Baseline in Body Weight | Change from baseline to week 24 (n=18, 11, 17) | -2.8 kilogram (kg) |
| Pradigastat (LCQ908) 10mg/20mg | Change From Baseline in Body Weight | Change from baseline to week 12 (n=20, 11, 17) | -2.4 kilogram (kg) |
| Pradigastat (LCQ908) 10mg/20mg | Change From Baseline in Body Weight | Change from baseline to week 24 (n=18, 11, 17) | -2.5 kilogram (kg) |
Secondary
Change From Baseline in Percentage of Fat in the Liver as Assessed Using MRI at Week 12
Patients were to undergo MRI three times during the course of the study to assess liver fat. Baseline is defined as the value collected at Week -2 MRI assessment (approximately between Day -7 to -14).
Time frame: From baseline to week 12
Population: Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with baseline and post-baseline value at week 12 are included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Percentage of Fat in the Liver as Assessed Using MRI at Week 12 | -0.80 Percentage of liver fat |
| Pradigastat (LCQ908) 5mg/10mg | Change From Baseline in Percentage of Fat in the Liver as Assessed Using MRI at Week 12 | -1.71 Percentage of liver fat |
| Pradigastat (LCQ908) 10mg/20mg | Change From Baseline in Percentage of Fat in the Liver as Assessed Using MRI at Week 12 | -2.98 Percentage of liver fat |
Secondary
Change From Baseline in Waist Circumference
Time frame: Baseline, 12 and 24 weeks
Population: Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with both baseline and post-baseline values at different timepoints were included in this endpoint analysis
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | Change From Baseline in Waist Circumference | Change from baseline to week 12 (n=20, 11, 17) | -0.4 centimeter (cm) |
| Placebo | Change From Baseline in Waist Circumference | Change from baseline to week 24 (n=19, 11, 17) | -1.7 centimeter (cm) |
| Pradigastat (LCQ908) 5mg/10mg | Change From Baseline in Waist Circumference | Change from baseline to week 12 (n=20, 11, 17) | -3.7 centimeter (cm) |
| Pradigastat (LCQ908) 5mg/10mg | Change From Baseline in Waist Circumference | Change from baseline to week 24 (n=19, 11, 17) | -3.7 centimeter (cm) |
| Pradigastat (LCQ908) 10mg/20mg | Change From Baseline in Waist Circumference | Change from baseline to week 12 (n=20, 11, 17) | -4.2 centimeter (cm) |
| Pradigastat (LCQ908) 10mg/20mg | Change From Baseline in Waist Circumference | Change from baseline to week 24 (n=19, 11, 17) | -4.2 centimeter (cm) |
Secondary
Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 12
Change from baseline ALT, AST and GGT values collected post-dose was analyzed using Mixed Model of Repeated Measurements (MMRM). Baseline is defined as the value collected at Week 0 (randomization). Treatment group and visit were fitted as factors and baseline was fitted as a continuous covariate.
Time frame: From Baseline to week 12
Population: Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with non-missing liver enzyme values at week 12 were included in this endpoint analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 12 | Liver enzyme: Aspartate aminotransferase (AST) | 5.7 U/L |
| Placebo | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 12 | Liver enzyme: Alanine aminotransferase (ALT) | -0.6 U/L |
| Placebo | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 12 | Liver enzyme: Gamma glutamyl transferase (GGT) | -0.4 U/L |
| Pradigastat (LCQ908) 5mg/10mg | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 12 | Liver enzyme: Alanine aminotransferase (ALT) | 2.9 U/L |
| Pradigastat (LCQ908) 5mg/10mg | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 12 | Liver enzyme: Gamma glutamyl transferase (GGT) | -6.0 U/L |
| Pradigastat (LCQ908) 5mg/10mg | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 12 | Liver enzyme: Aspartate aminotransferase (AST) | 8.9 U/L |
| Pradigastat (LCQ908) 10mg/20mg | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 12 | Liver enzyme: Aspartate aminotransferase (AST) | -0.1 U/L |
| Pradigastat (LCQ908) 10mg/20mg | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 12 | Liver enzyme: Gamma glutamyl transferase (GGT) | 12.0 U/L |
| Pradigastat (LCQ908) 10mg/20mg | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 12 | Liver enzyme: Alanine aminotransferase (ALT) | -3.7 U/L |
Secondary
Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 24
Change from baseline ALT, AST and GGT values collected post-dose was analyzed using Mixed Model of Repeated Measurements (MMRM). Baseline is defined as the value collected at Week 0 (randomization). Treatment group and visit were fitted as factors and baseline was fitted as a continuous covariate.
Time frame: From Baseline to week 24
Population: Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with non-missing liver enzyme values at week 24 were included in this endpoint analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 24 | Liver enzyme: Aspartate aminotransferase (AST) | -1.8 U/L |
| Placebo | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 24 | Liver enzyme: Alanine aminotransferase (ALT) | -5.3 U/L |
| Placebo | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 24 | Liver enzyme: Gamma glutamyl transferase (GGT) | -11.6 U/L |
| Pradigastat (LCQ908) 5mg/10mg | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 24 | Liver enzyme: Aspartate aminotransferase (AST) | 2.5 U/L |
| Pradigastat (LCQ908) 5mg/10mg | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 24 | Liver enzyme: Gamma glutamyl transferase (GGT) | -8.3 U/L |
| Pradigastat (LCQ908) 5mg/10mg | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 24 | Liver enzyme: Alanine aminotransferase (ALT) | -1.0 U/L |
| Pradigastat (LCQ908) 10mg/20mg | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 24 | Liver enzyme: Aspartate aminotransferase (AST) | -3.2 U/L |
| Pradigastat (LCQ908) 10mg/20mg | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 24 | Liver enzyme: Alanine aminotransferase (ALT) | -10.0 U/L |
| Pradigastat (LCQ908) 10mg/20mg | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 24 | Liver enzyme: Gamma glutamyl transferase (GGT) | 0.1 U/L |
Secondary
Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 6
Change from baseline ALT, AST and GGT values collected post-dose was analyzed using Mixed Model of Repeated Measurements (MMRM). Baseline is defined as the value collected at Week 0 (randomization). Treatment group and visit were fitted as factors and baseline was fitted as a continuous covariate.
Time frame: From Baseline to week 6
Population: Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with non-missing liver enzyme values at different timepoint were included in this endpoint analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 6 | Liver enzyme: Alanine aminotransferase (ALT) | -2.6 U/L |
| Placebo | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 6 | Liver enzyme: Aspartate aminotransferase (AST) | 2.9 U/L |
| Placebo | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 6 | Liver enzyme: Gamma glutamyl transferase (GGT) | -13.9 U/L |
| Pradigastat (LCQ908) 5mg/10mg | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 6 | Liver enzyme: Gamma glutamyl transferase (GGT) | -7.0 U/L |
| Pradigastat (LCQ908) 5mg/10mg | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 6 | Liver enzyme: Aspartate aminotransferase (AST) | 4.7 U/L |
| Pradigastat (LCQ908) 5mg/10mg | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 6 | Liver enzyme: Alanine aminotransferase (ALT) | 1.4 U/L |
| Pradigastat (LCQ908) 10mg/20mg | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 6 | Liver enzyme: Gamma glutamyl transferase (GGT) | -0.9 U/L |
| Pradigastat (LCQ908) 10mg/20mg | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 6 | Liver enzyme: Aspartate aminotransferase (AST) | -2.5 U/L |
| Pradigastat (LCQ908) 10mg/20mg | Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 6 | Liver enzyme: Alanine aminotransferase (ALT) | -9.1 U/L |
Secondary
Number of Patients With Adverse Events, Serious Adverse Events (SAEs) and Death as Assessment of Safety and Tolerability
Time frame: 24 weeks
Population: Safety set (SAF) - All patients who received at least one dose of study drug and had at least 1 post-baseline safety assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Patients With Adverse Events, Serious Adverse Events (SAEs) and Death as Assessment of Safety and Tolerability | Patients with at least one SAE | 3 Patients |
| Placebo | Number of Patients With Adverse Events, Serious Adverse Events (SAEs) and Death as Assessment of Safety and Tolerability | Patients with any adverse event | 14 Patients |
| Placebo | Number of Patients With Adverse Events, Serious Adverse Events (SAEs) and Death as Assessment of Safety and Tolerability | Death | 0 Patients |
| Pradigastat (LCQ908) 5mg/10mg | Number of Patients With Adverse Events, Serious Adverse Events (SAEs) and Death as Assessment of Safety and Tolerability | Patients with at least one SAE | 1 Patients |
| Pradigastat (LCQ908) 5mg/10mg | Number of Patients With Adverse Events, Serious Adverse Events (SAEs) and Death as Assessment of Safety and Tolerability | Death | 0 Patients |
| Pradigastat (LCQ908) 5mg/10mg | Number of Patients With Adverse Events, Serious Adverse Events (SAEs) and Death as Assessment of Safety and Tolerability | Patients with any adverse event | 9 Patients |
| Pradigastat (LCQ908) 10mg/20mg | Number of Patients With Adverse Events, Serious Adverse Events (SAEs) and Death as Assessment of Safety and Tolerability | Patients with any adverse event | 20 Patients |
| Pradigastat (LCQ908) 10mg/20mg | Number of Patients With Adverse Events, Serious Adverse Events (SAEs) and Death as Assessment of Safety and Tolerability | Death | 0 Patients |
| Pradigastat (LCQ908) 10mg/20mg | Number of Patients With Adverse Events, Serious Adverse Events (SAEs) and Death as Assessment of Safety and Tolerability | Patients with at least one SAE | 2 Patients |
Secondary
Percentage of Patients With Normalized Liver Enzymes
Normalized liver enzymes defined as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 40 U/L. Normal/High categories at baseline are defined by criteria of normal. Better is defined as high' at baseline and 'normal' post-dose; Same is defined as 'normal' at baseline and 'normal' post-dose or 'high' at baseline and 'high' post-dose; Worse is defined as 'normal' at baseline and 'high' post-dose.
Time frame: Baseline, week 6, week 12 and week 24
Population: Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with non-missing liver enzyme values at different timepoints were included in this endpoint analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Patients With Normalized Liver Enzymes | Better, week 12 | 5.0 Percentage of patients |
| Placebo | Percentage of Patients With Normalized Liver Enzymes | Same, week 24 | 89.5 Percentage of patients |
| Placebo | Percentage of Patients With Normalized Liver Enzymes | Same, week 6 | 85.0 Percentage of patients |
| Placebo | Percentage of Patients With Normalized Liver Enzymes | Same, week 12 | 90.0 Percentage of patients |
| Placebo | Percentage of Patients With Normalized Liver Enzymes | Worse, week 12 | 5.0 Percentage of patients |
| Placebo | Percentage of Patients With Normalized Liver Enzymes | Better, week 6 | 10.0 Percentage of patients |
| Placebo | Percentage of Patients With Normalized Liver Enzymes | Worse, week 24 | 5.3 Percentage of patients |
| Placebo | Percentage of Patients With Normalized Liver Enzymes | Worse, week 6 | 5.0 Percentage of patients |
| Placebo | Percentage of Patients With Normalized Liver Enzymes | Better, week 24 | 5.3 Percentage of patients |
| Pradigastat (LCQ908) 5mg/10mg | Percentage of Patients With Normalized Liver Enzymes | Same, week 24 | 72.7 Percentage of patients |
| Pradigastat (LCQ908) 5mg/10mg | Percentage of Patients With Normalized Liver Enzymes | Worse, week 6 | 9.1 Percentage of patients |
| Pradigastat (LCQ908) 5mg/10mg | Percentage of Patients With Normalized Liver Enzymes | Worse, week 24 | 9.1 Percentage of patients |
| Pradigastat (LCQ908) 5mg/10mg | Percentage of Patients With Normalized Liver Enzymes | Better, week 6 | 0.0 Percentage of patients |
| Pradigastat (LCQ908) 5mg/10mg | Percentage of Patients With Normalized Liver Enzymes | Better, week 12 | 9.1 Percentage of patients |
| Pradigastat (LCQ908) 5mg/10mg | Percentage of Patients With Normalized Liver Enzymes | Worse, week 12 | 18.2 Percentage of patients |
| Pradigastat (LCQ908) 5mg/10mg | Percentage of Patients With Normalized Liver Enzymes | Better, week 24 | 18.2 Percentage of patients |
| Pradigastat (LCQ908) 5mg/10mg | Percentage of Patients With Normalized Liver Enzymes | Same, week 6 | 90.9 Percentage of patients |
| Pradigastat (LCQ908) 5mg/10mg | Percentage of Patients With Normalized Liver Enzymes | Same, week 12 | 72.7 Percentage of patients |
| Pradigastat (LCQ908) 10mg/20mg | Percentage of Patients With Normalized Liver Enzymes | Worse, week 24 | 23.5 Percentage of patients |
| Pradigastat (LCQ908) 10mg/20mg | Percentage of Patients With Normalized Liver Enzymes | Same, week 6 | 85.0 Percentage of patients |
| Pradigastat (LCQ908) 10mg/20mg | Percentage of Patients With Normalized Liver Enzymes | Worse, week 6 | 5.0 Percentage of patients |
| Pradigastat (LCQ908) 10mg/20mg | Percentage of Patients With Normalized Liver Enzymes | Better, week 12 | 17.6 Percentage of patients |
| Pradigastat (LCQ908) 10mg/20mg | Percentage of Patients With Normalized Liver Enzymes | Better, week 24 | 17.6 Percentage of patients |
| Pradigastat (LCQ908) 10mg/20mg | Percentage of Patients With Normalized Liver Enzymes | Same, week 12 | 64.7 Percentage of patients |
| Pradigastat (LCQ908) 10mg/20mg | Percentage of Patients With Normalized Liver Enzymes | Worse, week 12 | 17.6 Percentage of patients |
| Pradigastat (LCQ908) 10mg/20mg | Percentage of Patients With Normalized Liver Enzymes | Same, week 24 | 58.8 Percentage of patients |
| Pradigastat (LCQ908) 10mg/20mg | Percentage of Patients With Normalized Liver Enzymes | Better, week 6 | 10.0 Percentage of patients |
Secondary
Percentage of Responders at Week 12
The response criteria are defined as: a. A reduction of ≥ 30% from baseline in liver fat b. A reduction of ≥ 50% from baseline in liver fat c. Liver fat content \< 10% d. Liver fat content \< 5.6%. Percentage is calculated as (m/n)\*100 where m: number of patients who are responders. n: number of patients with non-missing percent liver fat at that visit.
Time frame: At week 12
Population: Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with non-missing percent liver fat at week 12 were included in this endpoint analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Responders at Week 12 | At least 30% reduction in percent liver fat | 10.00 Percentage of responders |
| Placebo | Percentage of Responders at Week 12 | Liver fat content <5.6% | 0.00 Percentage of responders |
| Placebo | Percentage of Responders at Week 12 | At least 50% reduction in percent liver fat | 5.00 Percentage of responders |
| Placebo | Percentage of Responders at Week 12 | Liver fat content < 10% | 5.00 Percentage of responders |
| Pradigastat (LCQ908) 5mg/10mg | Percentage of Responders at Week 12 | At least 30% reduction in percent liver fat | 18.18 Percentage of responders |
| Pradigastat (LCQ908) 5mg/10mg | Percentage of Responders at Week 12 | Liver fat content < 10% | 18.18 Percentage of responders |
| Pradigastat (LCQ908) 5mg/10mg | Percentage of Responders at Week 12 | At least 50% reduction in percent liver fat | 0.00 Percentage of responders |
| Pradigastat (LCQ908) 5mg/10mg | Percentage of Responders at Week 12 | Liver fat content <5.6% | 0.00 Percentage of responders |
| Pradigastat (LCQ908) 10mg/20mg | Percentage of Responders at Week 12 | Liver fat content <5.6% | 21.05 Percentage of responders |
| Pradigastat (LCQ908) 10mg/20mg | Percentage of Responders at Week 12 | At least 30% reduction in percent liver fat | 31.58 Percentage of responders |
| Pradigastat (LCQ908) 10mg/20mg | Percentage of Responders at Week 12 | At least 50% reduction in percent liver fat | 21.05 Percentage of responders |
| Pradigastat (LCQ908) 10mg/20mg | Percentage of Responders at Week 12 | Liver fat content < 10% | 36.84 Percentage of responders |
Secondary
Percentage of Responders at Week 24
The response criteria are defined as: a. A reduction of ≥ 30% from baseline in liver fat b. A reduction of ≥ 50% from baseline in liver fat c. Liver fat content \< 10% d. Liver fat content \< 5.6%. Percentage is calculated as (m/n)\*100 where m: number of patients who are responders. n: number of patients with non-missing percent liver fat at that visit.
Time frame: From baseline to week 24
Population: Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with non-missing percent liver fat at week 24 were included in this endpoint analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Responders at Week 24 | Liver fat content < 10% | 5.26 Percentage of responders |
| Placebo | Percentage of Responders at Week 24 | At least 50% reduction in percent liver fat | 0.00 Percentage of responders |
| Placebo | Percentage of Responders at Week 24 | At least 30% reduction in percent liver fat | 10.53 Percentage of responders |
| Placebo | Percentage of Responders at Week 24 | Liver fat content <5.6% | 0.00 Percentage of responders |
| Pradigastat (LCQ908) 5mg/10mg | Percentage of Responders at Week 24 | At least 50% reduction in percent liver fat | 0.00 Percentage of responders |
| Pradigastat (LCQ908) 5mg/10mg | Percentage of Responders at Week 24 | At least 30% reduction in percent liver fat | 30.00 Percentage of responders |
| Pradigastat (LCQ908) 5mg/10mg | Percentage of Responders at Week 24 | Liver fat content < 10% | 20.00 Percentage of responders |
| Pradigastat (LCQ908) 5mg/10mg | Percentage of Responders at Week 24 | Liver fat content <5.6% | 0.00 Percentage of responders |
| Pradigastat (LCQ908) 10mg/20mg | Percentage of Responders at Week 24 | Liver fat content < 10% | 52.94 Percentage of responders |
| Pradigastat (LCQ908) 10mg/20mg | Percentage of Responders at Week 24 | At least 50% reduction in percent liver fat | 17.65 Percentage of responders |
| Pradigastat (LCQ908) 10mg/20mg | Percentage of Responders at Week 24 | At least 30% reduction in percent liver fat | 35.29 Percentage of responders |
| Pradigastat (LCQ908) 10mg/20mg | Percentage of Responders at Week 24 | Liver fat content <5.6% | 17.65 Percentage of responders |
Secondary
Percent Change From Baseline in Fasting Triglycerides
Blood samples were collected for a fasting triglycerides (TG) after a 10-hour (overnight) fast. Adjusted geometric means which is reported are calculated by back-transforming the adjusted means from the model and expressing as a percentage change from baseline. Baseline is defined as the value collected at Week 0 (randomization).
Time frame: Baseline, 6, 12 and 24 weeks
Population: Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with non-missing values at different timepoints were included in this endpoint analysis
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Fasting Triglycerides | Change From Baseline to week 24 (n= 19,11,17) | 13.0 percent change |
| Placebo | Percent Change From Baseline in Fasting Triglycerides | Change From Baseline to week 6 (n= 20,11, 20) | -14.6 percent change |
| Placebo | Percent Change From Baseline in Fasting Triglycerides | Change From Baseline to week 12 (n = 20,11,17) | -7.3 percent change |
| Pradigastat (LCQ908) 5mg/10mg | Percent Change From Baseline in Fasting Triglycerides | Change From Baseline to week 24 (n= 19,11,17) | -10.0 percent change |
| Pradigastat (LCQ908) 5mg/10mg | Percent Change From Baseline in Fasting Triglycerides | Change From Baseline to week 12 (n = 20,11,17) | -7.9 percent change |
| Pradigastat (LCQ908) 5mg/10mg | Percent Change From Baseline in Fasting Triglycerides | Change From Baseline to week 6 (n= 20,11, 20) | -16.0 percent change |
| Pradigastat (LCQ908) 10mg/20mg | Percent Change From Baseline in Fasting Triglycerides | Change From Baseline to week 24 (n= 19,11,17) | -2.4 percent change |
| Pradigastat (LCQ908) 10mg/20mg | Percent Change From Baseline in Fasting Triglycerides | Change From Baseline to week 12 (n = 20,11,17) | -15.8 percent change |
| Pradigastat (LCQ908) 10mg/20mg | Percent Change From Baseline in Fasting Triglycerides | Change From Baseline to week 6 (n= 20,11, 20) | 3.2 percent change |
Secondary
Post-prandial Peak Triglycerides Over 0 - 8 Hours
Post-prandial peak triglycerides is reported as maximum triglyceride value over 0-8 hours. Adjusted geometric means which is reported are calculated by back-transforming the adjusted means from the model. Baseline is defined as the value collected at Week 0 (randomization).
Time frame: Baseline, 6 and 24 weeks
Population: Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with non-missing values at different timepoints were included in this endpoint analysis
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Placebo | Post-prandial Peak Triglycerides Over 0 - 8 Hours | Week 6 (n = 20,11,20) | 336.0 mg/dL |
| Placebo | Post-prandial Peak Triglycerides Over 0 - 8 Hours | Baseline (n= 20, 11, 21) | 394.0 mg/dL |
| Placebo | Post-prandial Peak Triglycerides Over 0 - 8 Hours | Week 24 (n= 20, 11, 15) | 401.5 mg/dL |
| Pradigastat (LCQ908) 5mg/10mg | Post-prandial Peak Triglycerides Over 0 - 8 Hours | Week 6 (n = 20,11,20) | 309.7 mg/dL |
| Pradigastat (LCQ908) 5mg/10mg | Post-prandial Peak Triglycerides Over 0 - 8 Hours | Baseline (n= 20, 11, 21) | 370.2 mg/dL |
| Pradigastat (LCQ908) 5mg/10mg | Post-prandial Peak Triglycerides Over 0 - 8 Hours | Week 24 (n= 20, 11, 15) | 305.7 mg/dL |
| Pradigastat (LCQ908) 10mg/20mg | Post-prandial Peak Triglycerides Over 0 - 8 Hours | Baseline (n= 20, 11, 21) | 375.9 mg/dL |
| Pradigastat (LCQ908) 10mg/20mg | Post-prandial Peak Triglycerides Over 0 - 8 Hours | Week 24 (n= 20, 11, 15) | 351.8 mg/dL |
| Pradigastat (LCQ908) 10mg/20mg | Post-prandial Peak Triglycerides Over 0 - 8 Hours | Week 6 (n = 20,11,20) | 374.1 mg/dL |