A Randomized, Double-blind, Placebo Controlled, 3- Part, Adaptive Design, Multicenter Study to Assess Safety, Tolerability and Efficacy of Tropifexor (LJN452) in Patients With Non-alcoholic Steatohepatitis (NASH): FLIGHT-FXR
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 350
- 试验地点
- 1
- 主要终点
- Number of Nonalcoholic Steatohepatitis (NASH) Patients With Treatment Emergent Adverse Events (TEAE)
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
LJN452 30 μg
Tropifexor (LJN452) Part A
干预措施: Tropifexor (LJN452) (Drug)
LJN452 60 μg
Tropifezor (LJN452) Parts A + B
干预措施: Tropifexor (LJN452) (Drug)
LJN452 90 μg
Tropifexor (LJN452) Parts A + B
干预措施: Tropifexor (LJN452) (Drug)
Placebo A+ B
Placebo Parts A + B
干预措施: Placebo (Drug)
LJN452 140 μg
Tropifexor (LJN452) Part C
干预措施: Tropifexor (LJN452) (Drug)
LJN452 10 μg
Tropifexor (LJN452) Part A
干预措施: Tropifexor (LJN452) (Drug)
LJN452 200 μg
Tropifexor (LJN452) Part B
干预措施: Tropifexor (LJN452) (Drug)
Placebo C
Placebo Part C
干预措施: Placebo (Drug)
结局指标
主要结局
Number of Nonalcoholic Steatohepatitis (NASH) Patients With Treatment Emergent Adverse Events (TEAE)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
次要结局
- Change From Baseline in Weight(48 weeks)
- Change From Baseline in Biomarker FGF19(baseline, week 6)
- Change From Baseline in Biomarker C4(Week 6, 4 hours post dose)
- 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))
- 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))
- Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (Diagnostic Category)(EoT (Week 48))
- Change in Body Mass Index (BMI)(12 weeks)
- Change From Baseline in Waist to Hip (WTH) Ratio(12 weeks)
- 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)
- Change From Baseline on Markers of Liver Fibrosis, Fibrotest (Parts A+B)(End of Treatment (EoT):12 weeks)
- 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)
- Change From Baseline on Markers of Liver Fibrosis, Fibrotest, (Part C)(End of Treatment (EoT) was 48 weeks)
- 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)
- Itch Based on a Visual Analog Scale (VAS) Rating Scale(EoT for Parts A+B=12 weeks; EoT for Part C = 48 weeks)
- 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)
- C2h (Steady-state Drug Levels 2 Hours Postdose) of LJN452(Days 7 and 14 (10 and 30μg LJN452 C2h was not measured day 14))
- 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))
- Change From Baseline on Gamma-glutamyl Transferase (GGT)(EoT for Parts A+B=12 weeks; EoT for Part C = 48 weeks)
- Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (FDA, EMA)(EoT (Week 48))