Non-alcoholic Steatohepatitis (NASH)
Conditions
Keywords
LJN452, non-alcoholic steatohepatitis, NASH, phase 2, adaptive design, randomized
Brief summary
The purpose of the study was to assess the effects of different doses of tropifexor (LJN452) with respect to safety, tolerability, and on markers of liver inflammation in patients with NASH
Detailed description
Part A In Part A, 77 subjects were randomized at baseline to receive tropifexor (10 μg, 30 μg, 60 μg or 90 μg) or placebo (Arms A, B, C, D and E) for 12 weeks. After ≥ 90% of the subjects from Part A completed 8 weeks of treatment, the first interim analysis of all Part A data was performed and the Data Monitoring Committee (DMC) recommended evaluation of 90 μg tropifexor (safe andefficacious) in Part B. The treatment arms of Part A were completed through Week 16 without adaptation. Part B Randomization for Part B was started after the DMC recommendations on the dose to be used in Part B were implemented by the sponsor. As planned in the study protocol, since the first interim analysis selected one active dose (90 μg) to be tested in Part B, one of the other originally planned active treatment arms (60 μg) was included with a smaller sample size to confirm the earlier findings of this dose observed in Part A. Therefore, in Part B, 121 subjects, were randomized at baseline to receive tropifexor (90 μg and 60 μg) or placebo (Arms F, G and H) for 12 weeks. Part C was introduced as a result of the DMC recommendation to pursue doses \> 90 μg. Randomization in Part C started once the Part B randomization was completed. In Part C, 152 subjects were randomized at baseline to receive 140 μg or 200 μg tropifexor or placebo (Arms I, J and K) for 48 weeks. One patient was treated at 2 sites but is still only one patient. 350 total enrollment, and not 351.
Interventions
Comparison of different doses of drug
DRUGPlacebo
Comparator
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention model description
This was a randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose finding, 3-part (Parts A, B, and C), adaptive design study to assess the safety, tolerability, and efficacy of six doses of tropifexor as compared to placebo in subjects with NASH. Each study part had a screening period followed by a double-blind, randomized, treatment period, and a post-treatment follow-up period. This study was extended based on safety and efficacy results in Part A and available long-term toxicology coverage; Part C was added to explore 48 weeks of treatment at higher doses with paired biopsies in F2/3 NASH patients.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* male/female patients, 18 years or older * written informed consent * Part A and B patients : presence of NASH by histological evidence (liver biopsy obtained 2 years or less prior to randomization) with fibrosis level of F1, F2 or F3 (fibrosis in the absence of cirrhosis) and no diagnosis of chronic liver disease and elevated alanine aminotransferase (ALT) OR phenotypic diagnosis based on elevated ALT, BMI and diagnosis of Type 2 diabetes mellitus (DM) * Part C patients: presence of NASH by histological evidence (liver biopsy obtained during the Screening period or 6 months or less prior to randomization) with fibrosis level of F2 or F3 and no diagnosis of chronic liver disease And ( All Parts): * ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females) * Liver fat equal to or higher than 10% by MRI
Exclusion criteria
* previous exposure to OCA * patients taking prohibited medications * patients taking the following medicines UNLESS on a stable dose (within 25% of baseline dose) for at least 1 month before randomization: (for Part C patients, dose must be stable for at least 1 month prior to biopsy through Screening : anti- diabetic medications, insulin, beta-blockers, thiazide diuretics, fibrates, statins, niacin, ezetimibe, vitamin E (if doses \> 200 IU/day; doses \> 800 IU/day are prohibited), thyroid hormone, psychotropic medications, estrogen or estrogen containing birth control * pregnant or nursing (lactating) women * current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening * uncontrolled diabetes mellitus * new use of GLP-1 agonists such as liraglutide, exenatide, lixisenatide, albiglutide or dulaglutide within 3 months of screening * presence of cirrhosis * hepatic decompensation or severe liver impairment * previous diagnosis of other forms of chronic liver disease * patients with contraindications to MRI imaging
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Nonalcoholic Steatohepatitis (NASH) Patients With Treatment Emergent Adverse Events (TEAE) | End of Treatment (EoT): For Parts A&B, EoT was Week 12 (Primary Outcome Measure). For Part C, EoT was Week 48 (Secondary Outcome Measure) | Number of Nonalcoholic steatohepatitis (NASH) patients with TEAEs |
| Change in Transaminase Levels (ALT) | End of Treatment (EoT): For Parts A&B, EoT was Week 12 (Primary Outcome Measure). For Part C, EoT was Week 48 (Secondary Outcome Measure) | The alanine aminotransferase (ALT) test is a blood test that checks for liver damage. High levels of ALT may indicate liver damage. Normal range for ALT is typically 10 to 45 U/L or so (varies a little by age and gender). Elevation of these values indicate more liver inflammation/damage. ALT elevation is not unexpected in this patient population Dose relationship of tropifexor (LJN452) on ALT marker of hepatic inflammation in NASH from baseline to week 12 Summary statistics of change in ALT from baseline to EOT by treatment |
| Change in Aspartate Transaminase (AST) | End of Treatment (EoT): For Parts A&B, EoT was Week 12 (Primary Outcome Measure). For Part C, EoT was Week 48 (Secondary Outcome Measure) | To determine the dose relationship of tropifexor (LJN452) on markers of hepatic inflammation (AST) in NASH from baseline to Week 12 The alanine aminotransferase (AST) test is a blood test that checks for liver damage. High levels of AST may indicate liver damage. Normal range for AST is typically 10 to 45 U/L or so (varies a little by age and gender). Elevation of these values indicate more liver inflammation/damage AST elevation is not unexpected in this patient population The aspartate aminotransferase (AST) test is a blood test that checks for liver damage. Higher levels indicate more possible liver damage Summary statistics of change in AST from baseline up to end of treatment (EOT) |
| Change From Baseline in % of Fat in the Liver Assessed Using Magnetic Resonance Imaging (MRI) | End of Treatment (EoT): For Parts A&B, EoT was Week 12 (Primary Outcome Measure). For Part C, EoT was Week 48 (Secondary Outcome Measure) | Repeated measures analysis: Relative change in percentage of fat in the liver assessed using MRI from baseline by visit up to EOT (Full analysis set) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Biomarker C4 | Week 6, 4 hours post dose | Dose-response relationship of LJN452 on C4, a marker of hepatic target engagement at 4 hours post dose C4 (ng/mL): Summary statistics by treatment and visit |
| Change From Baseline on Gamma-glutamyl Transferase (GGT) | EoT for Parts A+B=12 weeks; EoT for Part C = 48 weeks | Summary statistics of change in GGT (IU/L) from baseline by visit up to EoT |
| Change From Baseline on Markers of Liver Fibrosis, Fibroscan | End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48 | Dose-response relationship of tropifexor (LJN452) on markers of liver fibrosis commonly available such as Fibroscan® Liver stiffness (kPa): Summary statistics by treatment and visit FibroScan is a specialized ultrasound machine for measuring fibrosis (scarring) in the liver Scores range from 0-4 with zero being no liver scarring and 4 being advanced liver scarring (cirrhosis) |
| Change From Baseline on Markers of Liver Fibrosis Panel (ELF) Score | End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48 | ANCOVA: LS Mean Change in Enhanced liver fibrosis panel (ELF) score from baseline by visit up to EOT. The total ELF score reference range calculated non-parametrically is 6.72 (90% CI 6.58-6.84) to 9.79 (90% CI 9.45-10.01); Journal of Hepatology 2013 vol. 59 j 236-242. Enhanced liver fibrosis Test (ELF) panel: the following was assessed: hyaluronic acid (HA), tissue inhibitor of metalloproteinases (TIMP-1), and amino-terminal pro-peptide of procollagen type III (PIIINP). The Enhanced Liver Fibrosis score is a linear combination of TIMP-1, PIIINP, and HA with the following formula: ELF score = 2.494+0.846 x ln(HA) + 0.735 x ln (PIIINP) + 0.391 x ln (TIMP-1). |
| Change From Baseline on Markers of Liver Fibrosis, Fibrotest (Parts A+B) | End of Treatment (EoT):12 weeks | Fibrosis biomarker test, originally called Fibrotest®/ Fibrosure®, is combines α2-macroglobulin (a2m), apolipoprotein A1 (aA1), total bilirubin (BIL), haptoglobin (h), GGT, and ALT. The coefficient for the score is calculated as: z = 4.467 x log(a2m) - 1.357 x log(h) + 1.017 x log(GGT) + 0.0281 x Age + 1.737 x log(BIL) - 1.184 x (aA1) + 0.301 x Gender - 5.54 where Gender = 1 for male and Gender = 0 for female. The score is then: 1/(1+e\^-z). Calculated scores range from 0.00 (no fibrosis) to 1.00 (severe fibrosis or cirrhosis) (See Part C in separate outcomes that follows) |
| Change From Baseline on Markers of Liver Fibrosis, Fibrotest, (Part C) | End of Treatment (EoT) was 48 weeks | Fibrosis biomarker test, originally called Fibrotest®/ Fibrosure®, is combines α2-macroglobulin (a2m), apolipoprotein A1 (aA1), total bilirubin (BIL), haptoglobin (h), GGT, and ALT. The coefficient for the score is calculated as: z = 4.467 x log(a2m) - 1.357 x log(h) + 1.017 x log(GGT) + 0.0281 x Age + 1.737 x log(BIL) - 1.184 x (aA1) + 0.301 x Gender - 5.54 where Gender = 1 for male and Gender = 0 for female. The score is then: 1/(1+e\^-z). Calculated scores range from 0.00 (no fibrosis) to 1.00 (severe fibrosis or cirrhosis) |
| Change From Baseline on Fasting Lipid Profile | End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48 | Repeated measures analysis: LS geometric mean ratio of fasting lipids to baseline by visit up to EOT |
| Change From Baseline in Weight | 48 weeks | Repeated measures for LS mean change in weight after 12 weeks of treatment |
| Pre-dose Trough Concentration (Ctrough) of LJN452 | In Parts A and B, LJN452 Ctrough was measured on Study Days 7, 14, 28, 42, 56, and 84. In Part C LJN452 Ctrough was measured on Study Days 42, 84, 168, 280 and 336 | Pre-dose Trough Concentration (Ctrough) of tropifexor (LJN452) |
| C2h (Steady-state Drug Levels 2 Hours Postdose) of LJN452 | Days 7 and 14 (10 and 30μg LJN452 C2h was not measured day 14) | Summary C2h of tropifexor (LJN452) |
| Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening of Steatohepatitis (Part C) - Total Score | EoT (Week 48) | Number of patients who have at least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (total score) |
| Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - FDA | EoT (Week 48) | Number of patients who have at least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (FDA) |
| Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - EMA | EoT (Week 48) | Number of patients who have at least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (EMA) |
| Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (Diagnostic Category) | EoT (Week 48) | Resolution of steatohepatitis (diagnostic category) without worsening of fibrosis (NASH CRN staging) |
| Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (FDA, EMA) | EoT (Week 48) | Resolution of steatohepatitis (diagnostic category) without worsening of fibrosis (NASH CRN staging) |
| Itch Based on a Visual Analog Scale (VAS) Rating Scale | EoT for Parts A+B=12 weeks; EoT for Part C = 48 weeks | Repeated measures analysis: Change in VAS for Itch from baseline by visit up to EoT VAS score 0 = no disease; and 9 is severely advanced disease |
| Change in Body Mass Index (BMI) | 12 weeks | Repeated measures for the LS mean change in BMI after 12 weeks of treatment. Body mass index (BMI) is a measure of body fat based on height and weight |
| Change From Baseline in Waist to Hip (WTH) Ratio | 12 weeks | The LS mean change in waist to hip ratio after 12 weeks of treatment |
| Change From Baseline in Biomarker FGF19 | baseline, week 6 | Dose-response relationship of tropifexor (LJN452) on FGF19 over time, a marker of FXR target engagement in the gut. ANCOVA: Ratio of FGF19 (pg/mL) post-dose to pre-dose at Week 6 Value at 6 weeks minus value at baseline |
Countries
Argentina, Australia, Austria, Belgium, Canada, France, Germany, India, Italy, Japan, Netherlands, Singapore, Slovakia, South Korea, Spain, Taiwan, United States
Participant flow
Recruitment details
In total, 411 subjects were screened in Parts A and B of the study together. Of these, 198 subjects were deemed eligible to participate in the study and were subsequently randomized
Pre-assignment details
In Part A, 77 were randomized at baseline to receive tropifexor 10 μg (n=14), 30μg (n=16), 60 μg (n=16) or 90 μg (n=15) or placebo (n=16) In Part B, 121 were randomized at baseline to receive tropifexor 90 μg (n=70) and 60 μg (n=21) or placebo (n=30) 780 were screened in Part C. Of these 152 met eligibility criteria and were randomized to receive tropifexor 140 μg (n=50) or 200 μg (n=51) or placebo (n=51)
Participants by arm
| Arm | Count |
|---|---|
| LJN452 10 μg 10 micrograms of Tropifexor (Part A) | 14 |
| LJN452 30 μg 30 micrograms of Tropifexor (Part A) | 16 |
| LJN452 60 μg 60 micrograms of Tropifexor (Parts A+B) | 37 |
| LJN452 90 μg 90 micrograms of Tropifexor (Parts A + B) | 85 |
| Placebo A+B Placebo (Parts A+B) | 46 |
| LJN452 140 μg 140 micrograms of Tropifexor (Part C) | 50 |
| LJN452 200 μg 200 micrograms of Tropifexor (Part C) | 51 |
| Placebo C Placebo (Part C) | 51 |
| Total | 350 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Part C (Randomized Set) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 5 | 9 | 2 |
| Part C (Randomized Set) | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 |
| Part C (Randomized Set) | Physician Decision | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
| Part C (Randomized Set) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 5 | 4 | 3 |
| Parts A + B (Randomized Set) | Adverse Event | 0 | 0 | 0 | 4 | 0 | 0 | 0 | 0 |
| Parts A + B (Randomized Set) | Physician Decision | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
| Parts A + B (Randomized Set) | Withdrawal by Subject | 0 | 0 | 1 | 2 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | LJN452 200 μg | LJN452 140 μg | Placebo A+B | LJN452 90 μg | Total | Placebo C | LJN452 60 μg | LJN452 10 μg | LJN452 30 μg |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical Part C <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | — | — | — |
| Age, Categorical Part C >=65 years | 10 Participants | 10 Participants | — | 0 Participants | 28 Participants | 8 Participants | — | — | — |
| Age, Categorical Part C Between 18 and 65 years | 41 Participants | 40 Participants | — | 0 Participants | 124 Participants | 43 Participants | — | — | — |
| Age, Categorical Parts A + B <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Parts A + B >=65 years | 0 Participants | 0 Participants | 5 Participants | 13 Participants | 24 Participants | 0 Participants | 4 Participants | 0 Participants | 2 Participants |
| Age, Categorical Parts A + B Between 18 and 65 years | 0 Participants | 0 Participants | 41 Participants | 72 Participants | 174 Participants | 0 Participants | 33 Participants | 14 Participants | 14 Participants |
| Age, Continuous Part C | 55 years STANDARD_DEVIATION 10.8 | 56 years STANDARD_DEVIATION 11.41 | — | — | 55 years STANDARD_DEVIATION 11 | 54 years STANDARD_DEVIATION 11 | — | — | — |
| Age, Continuous Parts A + B | — | — | 51 years STANDARD_DEVIATION 12.3 | 51 years STANDARD_DEVIATION 13.4 | 51 years STANDARD_DEVIATION 12.8 | — | 50 years STANDARD_DEVIATION 12.5 | 48 years STANDARD_DEVIATION 11.7 | 49 years STANDARD_DEVIATION 14.4 |
| Race/Ethnicity, Customized Asian (Part C) | 10 Participants | 10 Participants | — | — | 28 Participants | 8 Participants | — | — | — |
| Race/Ethnicity, Customized Asian (Parts A + B) | — | — | 20 Participants | 31 Participants | 70 Participants | — | 12 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Black (Part C) | 0 Participants | 0 Participants | — | — | 1 Participants | 1 Participants | — | — | — |
| Race/Ethnicity, Customized Black (Parts A + B) | — | — | 0 Participants | 1 Participants | 1 Participants | — | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Caucasian (Part C) | 38 Participants | 37 Participants | — | — | 113 Participants | 38 Participants | — | — | — |
| Race/Ethnicity, Customized Caucasian (Parts A + B) | — | — | 25 Participants | 50 Participants | 122 Participants | — | 24 Participants | 12 Participants | 11 Participants |
| Race/Ethnicity, Customized Other (Part C) | 3 Participants | 2 Participants | — | — | 9 Participants | 4 Participants | — | — | — |
| Race/Ethnicity, Customized Other (Parts A + B) | — | — | 0 Participants | 2 Participants | 2 Participants | — | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Pacific Islander (Part C) | 0 Participants | 1 Participants | — | — | 1 Participants | 0 Participants | — | — | — |
| Race/Ethnicity, Customized Pacific Islander (Parts A + B) | — | — | 1 Participants | 0 Participants | 1 Participants | — | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown (Parts A+B) | — | — | — | 1 Participants | 3 Participants | — | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Part C Female | 29 Participants | 36 Participants | 0 Participants | 0 Participants | 97 Participants | 32 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Part C Male | 22 Participants | 14 Participants | 0 Participants | 0 Participants | 55 Participants | 19 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Parts A + B Female | 0 Participants | 0 Participants | 21 Participants | 47 Participants | 104 Participants | 0 Participants | 20 Participants | 9 Participants | 7 Participants |
| Sex: Female, Male Parts A + B Male | 0 Participants | 0 Participants | 25 Participants | 38 Participants | 94 Participants | 0 Participants | 17 Participants | 5 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 17 | 0 / 37 | 0 / 85 | 0 / 50 | 0 / 51 | 0 / 97 | 0 / 350 |
| other Total, other adverse events | 5 / 13 | 11 / 17 | 16 / 37 | 50 / 85 | 43 / 50 | 45 / 51 | 63 / 97 | 233 / 350 |
| serious Total, serious adverse events | 0 / 13 | 0 / 17 | 0 / 37 | 4 / 85 | 5 / 50 | 3 / 51 | 6 / 97 | 18 / 350 |
Outcome results
Primary
Change From Baseline in % of Fat in the Liver Assessed Using Magnetic Resonance Imaging (MRI)
Repeated measures analysis: Relative change in percentage of fat in the liver assessed using MRI from baseline by visit up to EOT (Full analysis set)
Time frame: End of Treatment (EoT): For Parts A&B, EoT was Week 12 (Primary Outcome Measure). For Part C, EoT was Week 48 (Secondary Outcome Measure)
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LJN452 10 μg | Change From Baseline in % of Fat in the Liver Assessed Using Magnetic Resonance Imaging (MRI) | -7.48 percentage of fat in the liver | Standard Error 6.174 |
| LJN452 30 μg | Change From Baseline in % of Fat in the Liver Assessed Using Magnetic Resonance Imaging (MRI) | -14.07 percentage of fat in the liver | Standard Error 5.661 |
| LJN452 60 μg | Change From Baseline in % of Fat in the Liver Assessed Using Magnetic Resonance Imaging (MRI) | -15.04 percentage of fat in the liver | Standard Error 3.754 |
| LJN452 90 μg | Change From Baseline in % of Fat in the Liver Assessed Using Magnetic Resonance Imaging (MRI) | -12.34 percentage of fat in the liver | Standard Error 2.482 |
| Placebo A+B | Change From Baseline in % of Fat in the Liver Assessed Using Magnetic Resonance Imaging (MRI) | -6.19 percentage of fat in the liver | Standard Error 3.381 |
| LJN452 140 μg | Change From Baseline in % of Fat in the Liver Assessed Using Magnetic Resonance Imaging (MRI) | -31.25 percentage of fat in the liver | Standard Error 5.228 |
| LNJ452 200 μg | Change From Baseline in % of Fat in the Liver Assessed Using Magnetic Resonance Imaging (MRI) | -39.54 percentage of fat in the liver | Standard Error 4.968 |
| Placebo Part C | Change From Baseline in % of Fat in the Liver Assessed Using Magnetic Resonance Imaging (MRI) | -3.58 percentage of fat in the liver | Standard Error 4.718 |
Comparison: 10 microgramsof Tropifexor - Change in percentage of fat in the liver Part Ap-value: 0.85395% CI: [-19.66, 4.7]ANCOVA
Comparison: 30 micrograms of Tropifexor - Change in percentage of fat in the liver Part Ap-value: 0.23295% CI: [-25.24, -2.91]ANCOVA
Comparison: 60 micrograms of Tropifexor - Change in percentage of fat in the liver Parts A+Bp-value: 0.07795% CI: [-22.45, -7.64]ANCOVA
Comparison: 90 micrograms of Tropifexor - Change in percentage of fat in the liver Parts A+Bp-value: 0.14195% CI: [-17.23, -7.44]ANCOVA
Comparison: 140 micrograms of Tropifexor - Change in percentage of fat in the liver Part Cp-value: <0.00195% CI: [-41.58, -20.92]ANCOVA
Comparison: 200 micrograms of Tropifexor - Change in percentage of fat in the liver Part Cp-value: <0.00195% CI: [-49.37, -29.71]ANCOVA
Comparison: 10 micrograms of Tropifexor - Change in percentage of fat in the liver Parts A+B+Cp-value: 0.87295% CI: [-19.06, 2.88]ANCOVA
Comparison: 30 micrograms of Tropifexor - Change in percentage of fat in the liver Parts A+B+Cp-value: 0.46595% CI: [-24.36, -3.91]ANCOVA
Comparison: 60 micrograms of Tropifexor - Change in percentage of fat in the liver Parts A+B+Cp-value: 0.22895% CI: [-21.75, -8.29]ANCOVA
Comparison: 90 micrograms - Change in percentage of fat in the liver Parts A+B+Cp-value: 0.3795% CI: [-17.04, -8.08]ANCOVA
Comparison: 140 micrograms - Change in percentage of fat in the liver Parts A+B+Cp-value: 0.02995% CI: [-24.51, -12.91]ANCOVA
Comparison: 200 micrograms of Tropifexor - Change in percentage of fat in the liver Parts A+B+Cp-value: <0.00195% CI: [-40.13, -28.64]ANCOVA
Primary
Change in Aspartate Transaminase (AST)
To determine the dose relationship of tropifexor (LJN452) on markers of hepatic inflammation (AST) in NASH from baseline to Week 12 The alanine aminotransferase (AST) test is a blood test that checks for liver damage. High levels of AST may indicate liver damage. Normal range for AST is typically 10 to 45 U/L or so (varies a little by age and gender). Elevation of these values indicate more liver inflammation/damage AST elevation is not unexpected in this patient population The aspartate aminotransferase (AST) test is a blood test that checks for liver damage. Higher levels indicate more possible liver damage Summary statistics of change in AST from baseline up to end of treatment (EOT)
Time frame: End of Treatment (EoT): For Parts A&B, EoT was Week 12 (Primary Outcome Measure). For Part C, EoT was Week 48 (Secondary Outcome Measure)
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LJN452 10 μg | Change in Aspartate Transaminase (AST) | -11.3 U/L | Standard Deviation 12.09 |
| LJN452 30 μg | Change in Aspartate Transaminase (AST) | -2.1 U/L | Standard Deviation 29.62 |
| LJN452 60 μg | Change in Aspartate Transaminase (AST) | -10.2 U/L | Standard Deviation 25.03 |
| LJN452 90 μg | Change in Aspartate Transaminase (AST) | -2.5 U/L | Standard Deviation 24.6 |
| Placebo A+B | Change in Aspartate Transaminase (AST) | -7.1 U/L | Standard Deviation 23.85 |
| LJN452 140 μg | Change in Aspartate Transaminase (AST) | -16.7 U/L | Standard Deviation 23.36 |
| LNJ452 200 μg | Change in Aspartate Transaminase (AST) | -13.3 U/L | Standard Deviation 20.14 |
| Placebo Part C | Change in Aspartate Transaminase (AST) | -13.1 U/L | Standard Deviation 29 |
Comparison: 10 micrograms of Tropifexor vs placebo (Part A)p-value: 0.72295% CI: [-22.9, 3]ANCOVA
Comparison: 30 micrograms of Tropifexor vs placebo (Part A)p-value: 0.46895% CI: [-14, 9.5]ANCOVA
Comparison: 60 micrograms of Tropifexor vs placebo (Parts A+B)p-value: 0.77495% CI: [-16.7, -1]ANCOVA
Comparison: 90 micrograms of Tropifexor vs placebo (Parts A+B)p-value: 0.13695% CI: [-6, 4.9]ANCOVA
Comparison: 140 micrograms of Tropifexor vs placebo (Part C)p-value: 0.14595% CI: [-23.9, -8.2]ANCOVA
Comparison: 200 micrograms of Tropifexor vs placebo (Part C)p-value: 0.23695% CI: [-24.2, -6.4]ANCOVA
Comparison: 10 micrograms of Tropifexor vs placebo (Parts A+B+ C)p-value: 0.78895% CI: [-18.7, 4.4]ANCOVA
Comparison: 30 micrograms of Tropifexor vs placebo (Parts A+B+ C)p-value: 0.41395% CI: [-10.2, 11]ANCOVA
Comparison: 60 micrograms of Tropifexor vs placebo (Parts A+B+ C)p-value: 0.83395% CI: [-13.4, 1]ANCOVA
Comparison: 90 micrograms of Tropifexor vs placebo (Parts A+B+ C)p-value: 0.06895% CI: [-3.2, 7.3]ANCOVA
Comparison: 140 micrograms of Tropifexor vs placebo (Parts A+B+ C)p-value: 0.26995% CI: [-6.6, 6.5]ANCOVA
Comparison: 200 micrograms of Tropifexor vs placebo (Parts A+B+ C)p-value: 0.77795% CI: [-10.5, 2.9]ANCOVA
Primary
Change in Transaminase Levels (ALT)
The alanine aminotransferase (ALT) test is a blood test that checks for liver damage. High levels of ALT may indicate liver damage. Normal range for ALT is typically 10 to 45 U/L or so (varies a little by age and gender). Elevation of these values indicate more liver inflammation/damage. ALT elevation is not unexpected in this patient population Dose relationship of tropifexor (LJN452) on ALT marker of hepatic inflammation in NASH from baseline to week 12 Summary statistics of change in ALT from baseline to EOT by treatment
Time frame: End of Treatment (EoT): For Parts A&B, EoT was Week 12 (Primary Outcome Measure). For Part C, EoT was Week 48 (Secondary Outcome Measure)
Population: Full analysis set (FAS): All subjects to whom study treatment had been assigned.~Following the intent-to-treat (ITT) principle, subjects were analyzed according to the treatment they have been assigned to at randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LJN452 10 μg | Change in Transaminase Levels (ALT) | -16.7 IU/L | Standard Deviation 17.53 |
| LJN452 30 μg | Change in Transaminase Levels (ALT) | -12.0 IU/L | Standard Deviation 35.99 |
| LJN452 60 μg | Change in Transaminase Levels (ALT) | -17.3 IU/L | Standard Deviation 28.12 |
| LJN452 90 μg | Change in Transaminase Levels (ALT) | -15.4 IU/L | Standard Deviation 30.32 |
| Placebo A+B | Change in Transaminase Levels (ALT) | -8.1 IU/L | Standard Deviation 29.37 |
| LJN452 140 μg | Change in Transaminase Levels (ALT) | -27.0 IU/L | Standard Deviation 30.24 |
| LNJ452 200 μg | Change in Transaminase Levels (ALT) | -28.7 IU/L | Standard Deviation 25.4 |
| Placebo Part C | Change in Transaminase Levels (ALT) | -11.7 IU/L | Standard Deviation 61.64 |
Comparison: 10 micrograms of Tropifexor vs placebo (Part A)p-value: 0.36295% CI: [-31.2, -0.6]ANCOVA
Comparison: 30 micrograms of Tropifexor vs placebo (Part A)p-value: 0.72995% CI: [-24.8, 3.3]ANCOVA
Comparison: 60 micrograms of Tropifexor vs placebo (Parts A + B)p-value: 0.17395% CI: [-25.8, -7.1]ANCOVA
Comparison: 90 micrograms of Tropifexor vs placebo (Parts A + B)p-value: 0.18595% CI: [-21.3, -8.5]ANCOVA
Comparison: 140 micrograms of Tropifexor (Part C) vs placebop-value: 0.0295% CI: [-46.9, -16.3]ANCOVA
Comparison: 200 micrograms of Tropifexor vs placebo (Part C)p-value: 0.0395% CI: [-50.6, -14.5]ANCOVA
Comparison: 10 micrograms of Tropifexor vs placebo (Parts A + B + C)p-value: 0.45695% CI: [-26.3, -0.4]ANCOVA
Comparison: 30 micrograms of Tropifexor vs placebo (Parts A + B + C)p-value: 0.96695% CI: [-19.5, 4.4]ANCOVA
Comparison: 60 micrograms of Tropifexor vs placebo (Parts A + B + C)p-value: 0.27595% CI: [-21.4, -5.2]ANCOVA
Comparison: 90 micrograms of Tropifexor vs placebo (Parts A + B + C)p-value: 0.30495% CI: [-17.6, -5.9]ANCOVA
Comparison: 140 micrograms of Tropifexor vs placebo (Parts A + B + C)p-value: 0.05795% CI: [-24.5, -9.8]ANCOVA
Comparison: 200 micrograms of Tropifexor vs placebo (Parts A + B + C)p-value: 0.00395% CI: [-30.5, -15.6]ANCOVA
Primary
Number of Nonalcoholic Steatohepatitis (NASH) Patients With Treatment Emergent Adverse Events (TEAE)
Number of Nonalcoholic steatohepatitis (NASH) patients with TEAEs
Time frame: End of Treatment (EoT): For Parts A&B, EoT was Week 12 (Primary Outcome Measure). For Part C, EoT was Week 48 (Secondary Outcome Measure)
Population: Safety analysis set (SAS) is all subjects who received at least one dose of drug and had at least one post-baseline safety assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LJN452 10 μg | Number of Nonalcoholic Steatohepatitis (NASH) Patients With Treatment Emergent Adverse Events (TEAE) | 5 Participants |
| LJN452 30 μg | Number of Nonalcoholic Steatohepatitis (NASH) Patients With Treatment Emergent Adverse Events (TEAE) | 11 Participants |
| LJN452 60 μg | Number of Nonalcoholic Steatohepatitis (NASH) Patients With Treatment Emergent Adverse Events (TEAE) | 24 Participants |
| LJN452 90 μg | Number of Nonalcoholic Steatohepatitis (NASH) Patients With Treatment Emergent Adverse Events (TEAE) | 61 Participants |
| Placebo A+B | Number of Nonalcoholic Steatohepatitis (NASH) Patients With Treatment Emergent Adverse Events (TEAE) | 31 Participants |
| LJN452 140 μg | Number of Nonalcoholic Steatohepatitis (NASH) Patients With Treatment Emergent Adverse Events (TEAE) | 49 Participants |
| LNJ452 200 μg | Number of Nonalcoholic Steatohepatitis (NASH) Patients With Treatment Emergent Adverse Events (TEAE) | 49 Participants |
| Placebo Part C | Number of Nonalcoholic Steatohepatitis (NASH) Patients With Treatment Emergent Adverse Events (TEAE) | 46 Participants |
Secondary
Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - EMA
Number of patients who have at least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (EMA)
Time frame: EoT (Week 48)
Population: Full analysis set (FAS)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LJN452 10 μg | Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - EMA | 11 Participants |
| LJN452 30 μg | Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - EMA | 11 Participants |
| LJN452 60 μg | Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - EMA | 12 Participants |
Comparison: At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (EMA)p-value: 195% CI: [-0.214, 0.233]Mixed Models Analysis
Comparison: At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (EMA)p-value: 0.807495% CI: [-0.196, 0.251]Mixed Models Analysis
Secondary
Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - FDA
Number of patients who have at least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (FDA)
Time frame: EoT (Week 48)
Population: Full analysis set (FAS)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LJN452 10 μg | Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - FDA | 11 Participants |
| LJN452 30 μg | Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - FDA | 11 Participants |
| LJN452 60 μg | Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - FDA | 11 Participants |
Comparison: At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (FDA)p-value: 0.80795% CI: [-0.191, 0.246]Mixed Models Analysis
Comparison: At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (FDA)p-value: 0.623395% CI: [-0.173, 0.273]Mixed Models Analysis
Secondary
Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening of Steatohepatitis (Part C) - Total Score
Number of patients who have at least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (total score)
Time frame: EoT (Week 48)
Population: Full analysis set (FAS)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LJN452 10 μg | Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening of Steatohepatitis (Part C) - Total Score | 11 Participants |
| LJN452 30 μg | Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening of Steatohepatitis (Part C) - Total Score | 11 Participants |
| LJN452 60 μg | Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening of Steatohepatitis (Part C) - Total Score | 12 Participants |
Comparison: At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (total score)p-value: 195% CI: [-0.214, 0.223]Mixed Models Analysis
Comparison: At least one point improvement in fibrosis (NASH CRN staging) without worsening of steatohepatitis (total score)p-value: 0.807495% CI: [-0.196, 0.251]Mixed Models Analysis
Secondary
Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (Diagnostic Category)
Resolution of steatohepatitis (diagnostic category) without worsening of fibrosis (NASH CRN staging)
Time frame: EoT (Week 48)
Population: Full analysis set (FAS)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LJN452 10 μg | Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (Diagnostic Category) | 4 Participants |
| LJN452 30 μg | Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (Diagnostic Category) | 7 Participants |
| LJN452 60 μg | Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (Diagnostic Category) | 3 Participants |
Comparison: Resolution of steatohepatitis (diagnostic category) without worsening of fibrosis (NASH CRN staging)p-value: 0.702895% CI: [-0.184, 0.252]Mixed Models Analysis
Comparison: Resolution of steatohepatitis (diagnostic category) without worsening of fibrosis (NASH CRN staging)p-value: 0.171395% CI: [-0.098, 0.345]Mixed Models Analysis
Secondary
Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (FDA, EMA)
Resolution of steatohepatitis (diagnostic category) without worsening of fibrosis (NASH CRN staging)
Time frame: EoT (Week 48)
Population: Full analysis set (FAS)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LJN452 10 μg | Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (FDA, EMA) | 0 Participants |
| LJN452 30 μg | Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (FDA, EMA) | 2 Participants |
| LJN452 60 μg | Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (FDA, EMA) | 0 Participants |
Comparison: Resolution of steatohepatitis (FDA, EMA) without worsening of fibrosis (NASH CRN staging)p-value: 0.203395% CI: [-0.168, 0.278]Mixed Models Analysis
Secondary
C2h (Steady-state Drug Levels 2 Hours Postdose) of LJN452
Summary C2h of tropifexor (LJN452)
Time frame: Days 7 and 14 (10 and 30μg LJN452 C2h was not measured day 14)
Population: FAS
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LJN452 10 μg | C2h (Steady-state Drug Levels 2 Hours Postdose) of LJN452 | Profile day 7 | 0.190 ng/mL | Standard Deviation 0.143 |
| LJN452 30 μg | C2h (Steady-state Drug Levels 2 Hours Postdose) of LJN452 | Profile day 7 | 0.702 ng/mL | Standard Deviation 0.399 |
| LJN452 60 μg | C2h (Steady-state Drug Levels 2 Hours Postdose) of LJN452 | Profile day 7 | 1.228 ng/mL | Standard Deviation 0.598 |
| LJN452 60 μg | C2h (Steady-state Drug Levels 2 Hours Postdose) of LJN452 | Profile day 14 | 1.344 ng/mL | Standard Deviation 0.727 |
| LJN452 90 μg | C2h (Steady-state Drug Levels 2 Hours Postdose) of LJN452 | Profile day 7 | 2.193 ng/mL | Standard Deviation 1.003 |
| LJN452 90 μg | C2h (Steady-state Drug Levels 2 Hours Postdose) of LJN452 | Profile day 14 | 2.001 ng/mL | Standard Deviation 1.053 |
Secondary
Change From Baseline in Biomarker C4
Dose-response relationship of LJN452 on C4, a marker of hepatic target engagement at 4 hours post dose C4 (ng/mL): Summary statistics by treatment and visit
Time frame: Week 6, 4 hours post dose
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LJN452 10 μg | Change From Baseline in Biomarker C4 | 38.82 ng/mL | Standard Deviation 25.765 |
| LJN452 30 μg | Change From Baseline in Biomarker C4 | 32.75 ng/mL | Standard Deviation 23.36 |
| LJN452 60 μg | Change From Baseline in Biomarker C4 | 28.38 ng/mL | Standard Deviation 13.394 |
| LJN452 90 μg | Change From Baseline in Biomarker C4 | 40.19 ng/mL | Standard Deviation 31.356 |
| Placebo A+B | Change From Baseline in Biomarker C4 | 47.70 ng/mL | Standard Deviation 25.524 |
| LJN452 140 μg | Change From Baseline in Biomarker C4 | 14.97 ng/mL | Standard Deviation 20.232 |
| LNJ452 200 μg | Change From Baseline in Biomarker C4 | 8.54 ng/mL | Standard Deviation 9.583 |
| Placebo Part C | Change From Baseline in Biomarker C4 | 38.40 ng/mL | Standard Deviation 24.552 |
Secondary
Change From Baseline in Biomarker FGF19
Dose-response relationship of tropifexor (LJN452) on FGF19 over time, a marker of FXR target engagement in the gut. ANCOVA: Ratio of FGF19 (pg/mL) post-dose to pre-dose at Week 6 Value at 6 weeks minus value at baseline
Time frame: baseline, week 6
Population: FAS
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| LJN452 10 μg | Change From Baseline in Biomarker FGF19 | 1.45 pg/mL |
| LJN452 30 μg | Change From Baseline in Biomarker FGF19 | 1.53 pg/mL |
| LJN452 60 μg | Change From Baseline in Biomarker FGF19 | 3.82 pg/mL |
| LJN452 90 μg | Change From Baseline in Biomarker FGF19 | 5.78 pg/mL |
| Placebo A+B | Change From Baseline in Biomarker FGF19 | 1.33 pg/mL |
| LJN452 140 μg | Change From Baseline in Biomarker FGF19 | 1.97 pg/mL |
| LNJ452 200 μg | Change From Baseline in Biomarker FGF19 | 2.23 pg/mL |
| Placebo Part C | Change From Baseline in Biomarker FGF19 | 1.22 pg/mL |
Secondary
Change From Baseline in Waist to Hip (WTH) Ratio
The LS mean change in waist to hip ratio after 12 weeks of treatment
Time frame: 12 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LJN452 10 μg | Change From Baseline in Waist to Hip (WTH) Ratio | -0.01 ratio | Standard Error 0.009 |
| LJN452 30 μg | Change From Baseline in Waist to Hip (WTH) Ratio | 0.00 ratio | Standard Error 0.008 |
| LJN452 60 μg | Change From Baseline in Waist to Hip (WTH) Ratio | -0.01 ratio | Standard Error 0.005 |
| LJN452 90 μg | Change From Baseline in Waist to Hip (WTH) Ratio | 0.00 ratio | Standard Error 0.004 |
| Placebo A+B | Change From Baseline in Waist to Hip (WTH) Ratio | 0.00 ratio | Standard Error 0.005 |
| LJN452 140 μg | Change From Baseline in Waist to Hip (WTH) Ratio | 0.00 ratio | Standard Error 0.008 |
| LNJ452 200 μg | Change From Baseline in Waist to Hip (WTH) Ratio | -0.01 ratio | Standard Error 0.007 |
| Placebo Part C | Change From Baseline in Waist to Hip (WTH) Ratio | -0.02 ratio | Standard Error 0.007 |
Comparison: 10 micrograms of Tropifexor (Part A) vs Placebop-value: 0.5395% CI: [-0.03, 0.01]Mixed Models Analysis
Comparison: 30 micrograms of Tropifexor (Part A) vs Placebop-value: 0.85795% CI: [-0.02, 0.01]Mixed Models Analysis
Comparison: 60 micrograms of Tropifexor (Part A) vs Placebop-value: 0.26295% CI: [-0.02, 0]Mixed Models Analysis
Comparison: 90 micrograms of Tropifexor (Parts A + B) vs Placebop-value: 0.32395% CI: [0, 0.01]Mixed Models Analysis
Comparison: 140 micrograms of Tropifexor (Part C) vs Placebop-value: 0.195% CI: [-0.02, 0.01]Mixed Models Analysis
Comparison: 200 micrograms of Tropifexor (Part C) vs Placebop-value: 0.69395% CI: [-0.03, 0]Mixed Models Analysis
Secondary
Change From Baseline in Weight
Repeated measures for LS mean change in weight after 12 weeks of treatment
Time frame: 48 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LJN452 10 μg | Change From Baseline in Weight | -1.79 kg | Standard Error 0.608 |
| LJN452 30 μg | Change From Baseline in Weight | -0.78 kg | Standard Error 0.567 |
| LJN452 60 μg | Change From Baseline in Weight | -1.05 kg | Standard Error 0.377 |
| LJN452 90 μg | Change From Baseline in Weight | -1.15 kg | Standard Error 0.253 |
| Placebo A+B | Change From Baseline in Weight | 0.00 kg | Standard Error 0.338 |
| LJN452 140 μg | Change From Baseline in Weight | -5.10 kg | Standard Error 0.988 |
| LNJ452 200 μg | Change From Baseline in Weight | -5.89 kg | Standard Error 1.002 |
| Placebo Part C | Change From Baseline in Weight | -2.48 kg | Standard Error 0.915 |
Comparison: 10 micrograms of Tropifexor (Part A) vs Placebop-value: 0.0195% CI: [-2.99, 0.59]Mixed Models Analysis
Comparison: 30 micrograms of Tropifexor (Part A) vs Placebop-value: 0.23795% CI: [-1.9, 0.34]Mixed Models Analysis
Comparison: 60 micrograms of Tropifexor (Parts A + B) vs Placebop-value: 0.03795% CI: [-1.8, 0.31]Mixed Models Analysis
Comparison: 90 micrograms of Tropifexor (Parts A + B) vs Placebop-value: 0.00795% CI: [-1.65, 0.65]Mixed Models Analysis
Comparison: 140 micrograms of Tropifexor (Part C) vs Placebop-value: 0.05395% CI: [-7.05, -3.14]Mixed Models Analysis
Comparison: 200 micrograms of Tropifexor (Part C) vs Placebop-value: 0.01395% CI: [-7.87, -3.91]Mixed Models Analysis
Secondary
Change From Baseline on Fasting Lipid Profile
Repeated measures analysis: LS geometric mean ratio of fasting lipids to baseline by visit up to EOT
Time frame: End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48
Population: FAS
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| LJN452 10 μg | Change From Baseline on Fasting Lipid Profile | LDL Cholesterol | 0.923 mmol/L |
| LJN452 10 μg | Change From Baseline on Fasting Lipid Profile | Cholesterol | 0.949 mmol/L |
| LJN452 10 μg | Change From Baseline on Fasting Lipid Profile | Triglycerides | 0.920 mmol/L |
| LJN452 10 μg | Change From Baseline on Fasting Lipid Profile | HDL Cholesterol | 1.019 mmol/L |
| LJN452 10 μg | Change From Baseline on Fasting Lipid Profile | LDL/HDL Ratio | 0.921 mmol/L |
| LJN452 10 μg | Change From Baseline on Fasting Lipid Profile | Free Glycerol | 1.0563 mmol/L |
| LJN452 10 μg | Change From Baseline on Fasting Lipid Profile | Free Fatty Acid | 1.082 mmol/L |
| LJN452 30 μg | Change From Baseline on Fasting Lipid Profile | Cholesterol | 1.003 mmol/L |
| LJN452 30 μg | Change From Baseline on Fasting Lipid Profile | Free Glycerol | 0.9376 mmol/L |
| LJN452 30 μg | Change From Baseline on Fasting Lipid Profile | HDL Cholesterol | 1.001 mmol/L |
| LJN452 30 μg | Change From Baseline on Fasting Lipid Profile | LDL Cholesterol | 1.044 mmol/L |
| LJN452 30 μg | Change From Baseline on Fasting Lipid Profile | LDL/HDL Ratio | 1.058 mmol/L |
| LJN452 30 μg | Change From Baseline on Fasting Lipid Profile | Free Fatty Acid | 0.864 mmol/L |
| LJN452 30 μg | Change From Baseline on Fasting Lipid Profile | Triglycerides | 0.919 mmol/L |
| LJN452 60 μg | Change From Baseline on Fasting Lipid Profile | LDL Cholesterol | 1.092 mmol/L |
| LJN452 60 μg | Change From Baseline on Fasting Lipid Profile | LDL/HDL Ratio | 1.139 mmol/L |
| LJN452 60 μg | Change From Baseline on Fasting Lipid Profile | Free Fatty Acid | 0.929 mmol/L |
| LJN452 60 μg | Change From Baseline on Fasting Lipid Profile | Triglycerides | 0.960 mmol/L |
| LJN452 60 μg | Change From Baseline on Fasting Lipid Profile | Free Glycerol | 0.9128 mmol/L |
| LJN452 60 μg | Change From Baseline on Fasting Lipid Profile | Cholesterol | 1.029 mmol/L |
| LJN452 60 μg | Change From Baseline on Fasting Lipid Profile | HDL Cholesterol | 0.961 mmol/L |
| LJN452 90 μg | Change From Baseline on Fasting Lipid Profile | Free Glycerol | 0.9915 mmol/L |
| LJN452 90 μg | Change From Baseline on Fasting Lipid Profile | Triglycerides | 1.048 mmol/L |
| LJN452 90 μg | Change From Baseline on Fasting Lipid Profile | LDL/HDL Ratio | 1.227 mmol/L |
| LJN452 90 μg | Change From Baseline on Fasting Lipid Profile | Free Fatty Acid | 0.947 mmol/L |
| LJN452 90 μg | Change From Baseline on Fasting Lipid Profile | Cholesterol | 1.029 mmol/L |
| LJN452 90 μg | Change From Baseline on Fasting Lipid Profile | LDL Cholesterol | 1.104 mmol/L |
| LJN452 90 μg | Change From Baseline on Fasting Lipid Profile | HDL Cholesterol | 0.897 mmol/L |
| Placebo A+B | Change From Baseline on Fasting Lipid Profile | HDL Cholesterol | 0.959 mmol/L |
| Placebo A+B | Change From Baseline on Fasting Lipid Profile | Cholesterol | 0.956 mmol/L |
| Placebo A+B | Change From Baseline on Fasting Lipid Profile | Triglycerides | 0.991 mmol/L |
| Placebo A+B | Change From Baseline on Fasting Lipid Profile | LDL Cholesterol | 0.943 mmol/L |
| Placebo A+B | Change From Baseline on Fasting Lipid Profile | LDL/HDL Ratio | 0.980 mmol/L |
| Placebo A+B | Change From Baseline on Fasting Lipid Profile | Free Glycerol | 0.9604 mmol/L |
| Placebo A+B | Change From Baseline on Fasting Lipid Profile | Free Fatty Acid | 0.936 mmol/L |
| LJN452 140 μg | Change From Baseline on Fasting Lipid Profile | HDL Cholesterol | 0.855 mmol/L |
| LJN452 140 μg | Change From Baseline on Fasting Lipid Profile | Free Fatty Acid | 1.072 mmol/L |
| LJN452 140 μg | Change From Baseline on Fasting Lipid Profile | LDL/HDL Ratio | 1.252 mmol/L |
| LJN452 140 μg | Change From Baseline on Fasting Lipid Profile | LDL Cholesterol | 1.056 mmol/L |
| LJN452 140 μg | Change From Baseline on Fasting Lipid Profile | Free Glycerol | 1.1115 mmol/L |
| LJN452 140 μg | Change From Baseline on Fasting Lipid Profile | Triglycerides | 1.070 mmol/L |
| LJN452 140 μg | Change From Baseline on Fasting Lipid Profile | Cholesterol | 1.032 mmol/L |
| LNJ452 200 μg | Change From Baseline on Fasting Lipid Profile | Triglycerides | 1.068 mmol/L |
| LNJ452 200 μg | Change From Baseline on Fasting Lipid Profile | Cholesterol | 1.071 mmol/L |
| LNJ452 200 μg | Change From Baseline on Fasting Lipid Profile | Free Glycerol | 0.9808 mmol/L |
| LNJ452 200 μg | Change From Baseline on Fasting Lipid Profile | LDL/HDL Ratio | 1.478 mmol/L |
| LNJ452 200 μg | Change From Baseline on Fasting Lipid Profile | Free Fatty Acid | 0.887 mmol/L |
| LNJ452 200 μg | Change From Baseline on Fasting Lipid Profile | LDL Cholesterol | 1.200 mmol/L |
| LNJ452 200 μg | Change From Baseline on Fasting Lipid Profile | HDL Cholesterol | 0.824 mmol/L |
| Placebo Part C | Change From Baseline on Fasting Lipid Profile | Free Fatty Acid | 0.977 mmol/L |
| Placebo Part C | Change From Baseline on Fasting Lipid Profile | HDL Cholesterol | 1.033 mmol/L |
| Placebo Part C | Change From Baseline on Fasting Lipid Profile | Free Glycerol | 0.9846 mmol/L |
| Placebo Part C | Change From Baseline on Fasting Lipid Profile | Cholesterol | 0.977 mmol/L |
| Placebo Part C | Change From Baseline on Fasting Lipid Profile | LDL Cholesterol | 0.973 mmol/L |
| Placebo Part C | Change From Baseline on Fasting Lipid Profile | LDL/HDL Ratio | 0.947 mmol/L |
| Placebo Part C | Change From Baseline on Fasting Lipid Profile | Triglycerides | 0.883 mmol/L |
Secondary
Change From Baseline on Gamma-glutamyl Transferase (GGT)
Summary statistics of change in GGT (IU/L) from baseline by visit up to EoT
Time frame: EoT for Parts A+B=12 weeks; EoT for Part C = 48 weeks
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LJN452 10 μg | Change From Baseline on Gamma-glutamyl Transferase (GGT) | 1.6 IU/L | Standard Error 10.93 |
| LJN452 30 μg | Change From Baseline on Gamma-glutamyl Transferase (GGT) | -29.9 IU/L | Standard Error 10.11 |
| LJN452 60 μg | Change From Baseline on Gamma-glutamyl Transferase (GGT) | -34.2 IU/L | Standard Error 6.7 |
| LJN452 90 μg | Change From Baseline on Gamma-glutamyl Transferase (GGT) | -45.7 IU/L | Standard Error 4.52 |
| Placebo A+B | Change From Baseline on Gamma-glutamyl Transferase (GGT) | -5.0 IU/L | Standard Error 6.1 |
| LJN452 140 μg | Change From Baseline on Gamma-glutamyl Transferase (GGT) | -35.2 IU/L | Standard Error 11.58 |
| LNJ452 200 μg | Change From Baseline on Gamma-glutamyl Transferase (GGT) | -29.9 IU/L | Standard Error 11.65 |
| Placebo Part C | Change From Baseline on Gamma-glutamyl Transferase (GGT) | 9.0 IU/L | Standard Error 10.72 |
Secondary
Change From Baseline on Markers of Liver Fibrosis, Fibroscan
Dose-response relationship of tropifexor (LJN452) on markers of liver fibrosis commonly available such as Fibroscan® Liver stiffness (kPa): Summary statistics by treatment and visit FibroScan is a specialized ultrasound machine for measuring fibrosis (scarring) in the liver Scores range from 0-4 with zero being no liver scarring and 4 being advanced liver scarring (cirrhosis)
Time frame: End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LJN452 10 μg | Change From Baseline on Markers of Liver Fibrosis, Fibroscan | 10.94 scores | Standard Deviation 5.314 |
| LJN452 30 μg | Change From Baseline on Markers of Liver Fibrosis, Fibroscan | 10.40 scores | Standard Deviation 7.663 |
| LJN452 60 μg | Change From Baseline on Markers of Liver Fibrosis, Fibroscan | 9.90 scores | Standard Deviation 4.095 |
| LJN452 90 μg | Change From Baseline on Markers of Liver Fibrosis, Fibroscan | 9.00 scores | Standard Deviation 4.152 |
| Placebo A+B | Change From Baseline on Markers of Liver Fibrosis, Fibroscan | 9.30 scores | Standard Deviation 4.676 |
| LJN452 140 μg | Change From Baseline on Markers of Liver Fibrosis, Fibroscan | 11.29 scores | Standard Deviation 3.677 |
| LNJ452 200 μg | Change From Baseline on Markers of Liver Fibrosis, Fibroscan | 12.03 scores | Standard Deviation 4.804 |
| Placebo Part C | Change From Baseline on Markers of Liver Fibrosis, Fibroscan | 11.26 scores | Standard Deviation 4.027 |
Secondary
Change From Baseline on Markers of Liver Fibrosis, Fibrotest, (Part C)
Fibrosis biomarker test, originally called Fibrotest®/ Fibrosure®, is combines α2-macroglobulin (a2m), apolipoprotein A1 (aA1), total bilirubin (BIL), haptoglobin (h), GGT, and ALT. The coefficient for the score is calculated as: z = 4.467 x log(a2m) - 1.357 x log(h) + 1.017 x log(GGT) + 0.0281 x Age + 1.737 x log(BIL) - 1.184 x (aA1) + 0.301 x Gender - 5.54 where Gender = 1 for male and Gender = 0 for female. The score is then: 1/(1+e\^-z). Calculated scores range from 0.00 (no fibrosis) to 1.00 (severe fibrosis or cirrhosis)
Time frame: End of Treatment (EoT) was 48 weeks
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LJN452 10 μg | Change From Baseline on Markers of Liver Fibrosis, Fibrotest, (Part C) | -0.42 scores | Standard Error 0.131 |
| LJN452 30 μg | Change From Baseline on Markers of Liver Fibrosis, Fibrotest, (Part C) | -0.44 scores | Standard Error 0.135 |
| LJN452 60 μg | Change From Baseline on Markers of Liver Fibrosis, Fibrotest, (Part C) | -0.17 scores | Standard Error 0.119 |
Secondary
Change From Baseline on Markers of Liver Fibrosis, Fibrotest (Parts A+B)
Fibrosis biomarker test, originally called Fibrotest®/ Fibrosure®, is combines α2-macroglobulin (a2m), apolipoprotein A1 (aA1), total bilirubin (BIL), haptoglobin (h), GGT, and ALT. The coefficient for the score is calculated as: z = 4.467 x log(a2m) - 1.357 x log(h) + 1.017 x log(GGT) + 0.0281 x Age + 1.737 x log(BIL) - 1.184 x (aA1) + 0.301 x Gender - 5.54 where Gender = 1 for male and Gender = 0 for female. The score is then: 1/(1+e\^-z). Calculated scores range from 0.00 (no fibrosis) to 1.00 (severe fibrosis or cirrhosis) (See Part C in separate outcomes that follows)
Time frame: End of Treatment (EoT):12 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LJN452 10 μg | Change From Baseline on Markers of Liver Fibrosis, Fibrotest (Parts A+B) | -0.23 scores | Standard Deviation 0.284 |
| LJN452 30 μg | Change From Baseline on Markers of Liver Fibrosis, Fibrotest (Parts A+B) | -1.49 scores | Standard Deviation 0.852 |
| LJN452 60 μg | Change From Baseline on Markers of Liver Fibrosis, Fibrotest (Parts A+B) | -1.44 scores | Standard Deviation 1.08 |
| LJN452 90 μg | Change From Baseline on Markers of Liver Fibrosis, Fibrotest (Parts A+B) | -1.34 scores | Standard Deviation 1.222 |
| Placebo A+B | Change From Baseline on Markers of Liver Fibrosis, Fibrotest (Parts A+B) | -1.23 scores | Standard Deviation 1.088 |
Secondary
Change From Baseline on Markers of Liver Fibrosis Panel (ELF) Score
ANCOVA: LS Mean Change in Enhanced liver fibrosis panel (ELF) score from baseline by visit up to EOT. The total ELF score reference range calculated non-parametrically is 6.72 (90% CI 6.58-6.84) to 9.79 (90% CI 9.45-10.01); Journal of Hepatology 2013 vol. 59 j 236-242. Enhanced liver fibrosis Test (ELF) panel: the following was assessed: hyaluronic acid (HA), tissue inhibitor of metalloproteinases (TIMP-1), and amino-terminal pro-peptide of procollagen type III (PIIINP). The Enhanced Liver Fibrosis score is a linear combination of TIMP-1, PIIINP, and HA with the following formula: ELF score = 2.494+0.846 x ln(HA) + 0.735 x ln (PIIINP) + 0.391 x ln (TIMP-1).
Time frame: End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LJN452 10 μg | Change From Baseline on Markers of Liver Fibrosis Panel (ELF) Score | 0.05 scores on a scale | Standard Error 0.158 |
| LJN452 30 μg | Change From Baseline on Markers of Liver Fibrosis Panel (ELF) Score | 0.00 scores on a scale | Standard Error 0.146 |
| LJN452 60 μg | Change From Baseline on Markers of Liver Fibrosis Panel (ELF) Score | -0.19 scores on a scale | Standard Error 0.097 |
| LJN452 90 μg | Change From Baseline on Markers of Liver Fibrosis Panel (ELF) Score | 0.20 scores on a scale | Standard Error 0.064 |
| Placebo A+B | Change From Baseline on Markers of Liver Fibrosis Panel (ELF) Score | 0.08 scores on a scale | Standard Error 0.087 |
| LJN452 140 μg | Change From Baseline on Markers of Liver Fibrosis Panel (ELF) Score | -0.34 scores on a scale | Standard Error 0.132 |
| LNJ452 200 μg | Change From Baseline on Markers of Liver Fibrosis Panel (ELF) Score | -0.24 scores on a scale | Standard Error 0.122 |
| Placebo Part C | Change From Baseline on Markers of Liver Fibrosis Panel (ELF) Score | -0.08 scores on a scale | Standard Error 0.115 |
Secondary
Change in Body Mass Index (BMI)
Repeated measures for the LS mean change in BMI after 12 weeks of treatment. Body mass index (BMI) is a measure of body fat based on height and weight
Time frame: 12 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LJN452 10 μg | Change in Body Mass Index (BMI) | -0.64 kg/m2 | Standard Error 0.208 |
| LJN452 30 μg | Change in Body Mass Index (BMI) | -0.29 kg/m2 | Standard Error 0.194 |
| LJN452 60 μg | Change in Body Mass Index (BMI) | -0.35 kg/m2 | Standard Error 0.129 |
| LJN452 90 μg | Change in Body Mass Index (BMI) | -0.42 kg/m2 | Standard Error 0.087 |
| Placebo A+B | Change in Body Mass Index (BMI) | 0.02 kg/m2 | Standard Error 0.116 |
| LJN452 140 μg | Change in Body Mass Index (BMI) | -1.88 kg/m2 | Standard Error 0.322 |
| LNJ452 200 μg | Change in Body Mass Index (BMI) | -2.11 kg/m2 | Standard Error 0.327 |
| Placebo Part C | Change in Body Mass Index (BMI) | -0.80 kg/m2 | Standard Error 0.299 |
Comparison: 10 micrograms of Tropifexor (Part A) vs Placebop-value: 0.00695% CI: [-1.05, 0.23]Mixed Models Analysis
Comparison: 30 micrograms of Tropifexor (Part A) vs Placebop-value: 0.17795% CI: [-0.67, 0.09]Mixed Models Analysis
Comparison: 60 micrograms of Tropifexor (Parts A + B) vs Placebop-value: 0.03295% CI: [-0.61, 0.1]Mixed Models Analysis
Comparison: 90 micrograms of Tropifexor (Parts A + B) vs Placebop-value: 0.00395% CI: [-0.59, 0.25]Mixed Models Analysis
Comparison: 140 micrograms of Tropifexor (Part C) vs Placebop-value: 0.01595% CI: [-2.51, -1.24]Mixed Models Analysis
Comparison: 200 micrograms of Tropifexor (Part C) vs Placebop-value: 0.00495% CI: [-2.75, -1.46]Mixed Models Analysis
Secondary
Itch Based on a Visual Analog Scale (VAS) Rating Scale
Repeated measures analysis: Change in VAS for Itch from baseline by visit up to EoT VAS score 0 = no disease; and 9 is severely advanced disease
Time frame: EoT for Parts A+B=12 weeks; EoT for Part C = 48 weeks
Population: FAS
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LJN452 10 μg | Itch Based on a Visual Analog Scale (VAS) Rating Scale | -0.3 scores | Standard Error 0.48 |
| LJN452 30 μg | Itch Based on a Visual Analog Scale (VAS) Rating Scale | 0.2 scores | Standard Error 0.43 |
| LJN452 60 μg | Itch Based on a Visual Analog Scale (VAS) Rating Scale | 0.4 scores | Standard Error 0.28 |
| LJN452 90 μg | Itch Based on a Visual Analog Scale (VAS) Rating Scale | 0.1 scores | Standard Error 0.19 |
| Placebo A+B | Itch Based on a Visual Analog Scale (VAS) Rating Scale | 0.6 scores | Standard Error 0.27 |
| LJN452 140 μg | Itch Based on a Visual Analog Scale (VAS) Rating Scale | 0.6 scores | Standard Error 0.37 |
| LNJ452 200 μg | Itch Based on a Visual Analog Scale (VAS) Rating Scale | 1.1 scores | Standard Error 0.35 |
| Placebo Part C | Itch Based on a Visual Analog Scale (VAS) Rating Scale | 0.3 scores | Standard Error 0.33 |
Secondary
Pre-dose Trough Concentration (Ctrough) of LJN452
Pre-dose Trough Concentration (Ctrough) of tropifexor (LJN452)
Time frame: In Parts A and B, LJN452 Ctrough was measured on Study Days 7, 14, 28, 42, 56, and 84. In Part C LJN452 Ctrough was measured on Study Days 42, 84, 168, 280 and 336
Population: FAS
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LJN452 10 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 56 | 0.168 ng/mL | Standard Deviation 0.088 |
| LJN452 10 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 28 | 0.118 ng/mL | Standard Deviation 0.087 |
| LJN452 10 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 84 | 0.118 ng/mL | Standard Deviation 0.08 |
| LJN452 10 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 14 | 0.216 ng/mL | Standard Deviation 0.127 |
| LJN452 10 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 7 | 0.142 ng/mL | Standard Deviation 0.119 |
| LJN452 10 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 42 | 0.161 ng/mL | Standard Deviation 0.094 |
| LJN452 30 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 28 | 0.411 ng/mL | Standard Deviation 0.25 |
| LJN452 30 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 42 | 0.382 ng/mL | Standard Deviation 0.15 |
| LJN452 30 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 7 | 0.355 ng/mL | Standard Deviation 0.194 |
| LJN452 30 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 14 | 0.505 ng/mL | Standard Deviation 0.328 |
| LJN452 30 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 84 | 0.366 ng/mL | Standard Deviation 0.147 |
| LJN452 30 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 56 | 0.474 ng/mL | Standard Deviation 0.273 |
| LJN452 60 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 42 | 0.647 ng/mL | Standard Deviation 0.344 |
| LJN452 60 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 7 | 0.638 ng/mL | Standard Deviation 0.453 |
| LJN452 60 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 14 | 0.626 ng/mL | Standard Deviation 0.281 |
| LJN452 60 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 28 | 0.639 ng/mL | Standard Deviation 0.265 |
| LJN452 60 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 56 | 0.637 ng/mL | Standard Deviation 0.278 |
| LJN452 60 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 84 | 0.530 ng/mL | Standard Deviation 0.357 |
| LJN452 90 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 28 | 1.027 ng/mL | Standard Deviation 0.7 |
| LJN452 90 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 7 | 1.215 ng/mL | Standard Deviation 0.593 |
| LJN452 90 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 56 | 1.041 ng/mL | Standard Deviation 0.701 |
| LJN452 90 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 14 | 1.115 ng/mL | Standard Deviation 0.693 |
| LJN452 90 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 84 | 1.095 ng/mL | Standard Deviation 0.653 |
| LJN452 90 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 42 | 1.032 ng/mL | Standard Deviation 0.661 |
| Placebo A+B | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 168 | 1.889 ng/mL | Standard Deviation 1.34 |
| Placebo A+B | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 280 | 2.129 ng/mL | Standard Deviation 1.257 |
| Placebo A+B | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 42 | 2.821 ng/mL | Standard Deviation 1.659 |
| Placebo A+B | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 84 | 1.685 ng/mL | Standard Deviation 0.874 |
| Placebo A+B | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 336 | 1.444 ng/mL | Standard Deviation 1.077 |
| LJN452 140 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 336 | 1.979 ng/mL | Standard Deviation 1.153 |
| LJN452 140 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 42 | 3.533 ng/mL | Standard Deviation 2.356 |
| LJN452 140 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 84 | 2.286 ng/mL | Standard Deviation 1.259 |
| LJN452 140 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 168 | 2.146 ng/mL | Standard Deviation 1.383 |
| LJN452 140 μg | Pre-dose Trough Concentration (Ctrough) of LJN452 | Profile day 280 | 1.990 ng/mL | Standard Deviation 1.053 |