Clinical Trials List
Protocol NumberCLJN452A2202
NCT Number(ClinicalTrials.gov Identfier)NCT02855164
2016-07-01 - 2020-01-31
Others
Terminated6
ICD-10K75.81
Nonalcoholic steatohepatitis (NASH)
ICD-9571.8
Other chronic nonalcoholic liver disease
A randomized, double-blind, placebo controlled, 2- part, adaptive design, multicenter 12-week study to assess safety, tolerability and efficacy of LJN452 in patients with non-alcoholic steatohepatitis (NASH)
-
Trial Applicant
NOVARTIS (TAIWAN) CO., LTD.
-
Sponsor
Novartis Pharmaceuticals
-
Trial scale
Multi-Regional Multi-Center
-
Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- 曾振輝 Digestive System Department
- 陳聰興 Digestive System Department
- Yi-Chung Hsieh Digestive System Department
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- 王苑貞 Digestive System Department
- Teh-Ia Huo Digestive System Department
- 藍耿欣 Digestive System Department
- Chin-Sung Kuo Division of Endocrinology
- 李癸汌 Digestive System Department
- Chien-Wei Su Digestive System Department
- 黃惠君 Digestive System Department
- Chi-Jen Chu Digestive System Department
- 黃以信 Digestive System Department
The Actual Total Number of Participants Enrolled
4 Terminated
Audit
None
Co-Principal Investigator
- Chia-Yen Dai Digestive System Department
- Ming-Lun Yeh Digestive System Department
- Wan-Long Chuang Digestive System Department
- 黃駿逸 Digestive System Department
- Ming-Lung Yu Digestive System Department
- Chung-Feng Huang Digestive System Department
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Hung-Yao Chen Digestive System Department
- Po-Heng Chuang Digestive System Department
- 蘇文邦 Digestive System Department
- Hung-Wei Wang Digestive System Department
- Hsueh-Chou Lai Digestive System Department
- 陳昇弘 Digestive System Department
- Wei-Fan Hsu Digestive System Department
The Actual Total Number of Participants Enrolled
0 Terminated
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
Audit
None
Co-Principal Investigator
Audit
None
Co-Principal Investigator
- Chun-Jen Liu Digestive System Department
- 洪俊銘 Digestive System Department
- 楊宏志 Digestive System Department
- BANG-BIN CHEN Digestive System Department
- PEI-JER CHEN Digestive System Department
- 蘇東弘 Digestive System Department
- Chen-Hua Liu Digestive System Department
The Actual Total Number of Participants Enrolled
0 Terminated
Condition/Disease
non-alcoholic steatohepatitis (NASH)
Objectives
The purpose of this study is to assess the safety and tolerability profile of LJN452 and to
determine the early hepatic response to different doses of LJN452 in patients with phenotypic nonalcoholic steatohepatitis (NASH). Data from this study will be used to support further
development of LJN452 in the treatment of patients with NASH.
Primary objective
To determine safety and tolerability of different doses of LJN452
To determine the dose-response relationship of LJN452 on markers of hepatic inflammation
in NASH (ALT and AST)
Secondary objectives
To determine the dose-response relationship of LJN452 on liver fat content by changes in
quantitative MRI determined fat
To determine the effect of different doses of LJN452 on anthropometric assessments (weight,
BMI, waist-to-hip (WTH) ratio) after 12 weeks of treatment
To determine the dose-response relationship of LJN452 on FGF19 over time, a marker of
FXR target engagement in the gut, and C4, a marker of hepatic target engagement
To determine the dose-response relationship of LJN452 on markers of liver fibrosis
commonly available such as Fibroscan® (in a subset of patients), enhanced liver fibrosis
panel (ELF), and fibrosis biomarker test (originally known as Fibrotest®/ FibroSure®)
To determine the dose-response relationship of LJN452 on GGT, a marker of cholestasis
To determine the effect of LJN452 on fasting lipid profile
To determine the pharmacokinetics (PK) of LJN452
To determine the effect of LJN452 compared to placebo with respect to occurrence of
potential itch based on a visual analog scale (VAS) rating scale
To determine effects of LJN452 on primary endpoints in the subset of patients who have
historical biopsy data, both overall and by subsets defined by fibrosis score and/or NAS
score as feasible (based on the extent of available data)
Test Drug
LJN452 (tropifexor)
Active Ingredient
tropifexor
Dosage Form
Capsule
Dosage
0.01mg,0.03mg,0.06mg,0.09mg,0.14mg,0.2mg
Endpoints
Primary Outcome Measures :
1. Number of Nonalcoholic Steatohepatitis (NASH) Patients With Treatment Emergent Adverse Events (TEAE) [ 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) ]
2. Change in Transaminase Levels (ALT) [ 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) ]
3. Change in Aspartate Transaminase (AST) [ 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) ]
4. Change From Baseline in % of Fat in the Liver Assessed Using Magnetic Resonance Imaging (MRI) [ 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) ]
Secondary Outcome Measures :
1. Change From Baseline in Weight [ Time Frame: 12 weeks ]
2. Change in Body Mass Index (BMI) [ Time Frame: 12 weeks ]
3. Change From Baseline in Waist to Hip (WTH) Ratio [ Time Frame: 12 weeks ]
4. Change From Baseline in Biomarker FGF19 [ Time Frame: baseline, week 6 ]
5. Change From Baseline in Biomarker C4 [ Time Frame: Week 6, 4 hours post dose ]
6. Change From Baseline on Markers of Liver Fibrosis, Fibroscan [ Time Frame: End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48 ]
7. Change From Baseline on Markers of Liver Fibrosis Panel (ELF) Score [ Time Frame: End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48 ]
8. Change From Baseline on Markers of Liver Fibrosis, Fibrotest (Parts A+B) [ Time Frame: End of Treatment (EoT):12 weeks ]
9. Change From Baseline on Markers of Liver Fibrosis, Fibrotest, (Part C) [ Time Frame: End of Treatment (EoT) was 48 weeks ]
10. Change From Baseline on Gamma-glutamyl Transferase (GGT) [ Time Frame: EoT for Parts A+B=12 weeks; EoT for Part C = 48 weeks ]
11. Change From Baseline on Fasting Lipid Profile [ Time Frame: End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48 ]
12. Itch Based on a Visual Analog Scale (VAS) Rating Scale [ Time Frame: EoT for Parts A+B=12 weeks; EoT for Part C = 48 weeks ]
13. Pre-dose Trough Concentration (Ctrough) of 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 ]
14. C2h (Steady-state Drug Levels 2 Hours Postdose) of LJN452 [ Time Frame: Days 7 and 14 (10 and 30μg LJN452 C2h was not measured day 14) ]
15. 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 [ Time Frame: EoT (Week 48) ]
16. Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - FDA [ Time Frame: EoT (Week 48) ]
17. Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - EMA [ Time Frame: EoT (Week 48) ]
18. Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (Diagnostic Category) [ Time Frame: EoT (Week 48) ]
19. Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (FDA, EMA) [ Time Frame: EoT (Week 48) ]
1. Number of Nonalcoholic Steatohepatitis (NASH) Patients With Treatment Emergent Adverse Events (TEAE) [ 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) ]
2. Change in Transaminase Levels (ALT) [ 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) ]
3. Change in Aspartate Transaminase (AST) [ 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) ]
4. Change From Baseline in % of Fat in the Liver Assessed Using Magnetic Resonance Imaging (MRI) [ 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) ]
Secondary Outcome Measures :
1. Change From Baseline in Weight [ Time Frame: 12 weeks ]
2. Change in Body Mass Index (BMI) [ Time Frame: 12 weeks ]
3. Change From Baseline in Waist to Hip (WTH) Ratio [ Time Frame: 12 weeks ]
4. Change From Baseline in Biomarker FGF19 [ Time Frame: baseline, week 6 ]
5. Change From Baseline in Biomarker C4 [ Time Frame: Week 6, 4 hours post dose ]
6. Change From Baseline on Markers of Liver Fibrosis, Fibroscan [ Time Frame: End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48 ]
7. Change From Baseline on Markers of Liver Fibrosis Panel (ELF) Score [ Time Frame: End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48 ]
8. Change From Baseline on Markers of Liver Fibrosis, Fibrotest (Parts A+B) [ Time Frame: End of Treatment (EoT):12 weeks ]
9. Change From Baseline on Markers of Liver Fibrosis, Fibrotest, (Part C) [ Time Frame: End of Treatment (EoT) was 48 weeks ]
10. Change From Baseline on Gamma-glutamyl Transferase (GGT) [ Time Frame: EoT for Parts A+B=12 weeks; EoT for Part C = 48 weeks ]
11. Change From Baseline on Fasting Lipid Profile [ Time Frame: End of Treatment (EoT): For Parts A&B, EoT was Week 12. For Part C, EoT was Week 48 ]
12. Itch Based on a Visual Analog Scale (VAS) Rating Scale [ Time Frame: EoT for Parts A+B=12 weeks; EoT for Part C = 48 weeks ]
13. Pre-dose Trough Concentration (Ctrough) of 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 ]
14. C2h (Steady-state Drug Levels 2 Hours Postdose) of LJN452 [ Time Frame: Days 7 and 14 (10 and 30μg LJN452 C2h was not measured day 14) ]
15. 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 [ Time Frame: EoT (Week 48) ]
16. Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - FDA [ Time Frame: EoT (Week 48) ]
17. Biopsy-based Response at Week 48 Compared to Baseline: At Least One Point Improvement in Fibrosis (NASH CRN Staging) Without Worsening - EMA [ Time Frame: EoT (Week 48) ]
18. Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (Diagnostic Category) [ Time Frame: EoT (Week 48) ]
19. Biopsy-based Response at Week 48 Compared to Baseline: Difference Between Treatment Groups (Part C) - Resolution of Steatohepatitis (FDA, EMA) [ Time Frame: EoT (Week 48) ]
Inclution Criteria
Inclusion criteria:
1. Written informed consent must be obtained before any assessment is performed
2. Male and female patients 18 years or older (at the time of the screening visit)
3. Presence of NASH as demonstrated by ONE of the following:
Histologic evidence of NASH based on liver biopsy obtained 2 years or less before
randomization with a diagnosis consistent with NASH, fibrosis level F1, F2 or F3, no
diagnosis of alternative chronic liver diseases AND
ALT ≥ 60 IU/L (males) or ≥ 40 IU/L (females)
OR
Phenotypic diagnosis of NASH based on presence of ALL THREE of the following:
o ALT ≥ 60 IU/L (males) or ≥ 40 IU/L (females) AND
o BMI ≥ 27 kg/m2
(in patients with a self-identified race other than Asian) or ≥ 23
kg/m2
(in patients with a self-identified Asian race) AND
o Diagnosis of Type 2 diabetes mellitus by having either:
- HbA1C ≥ 6.5% or
- Drug therapy for Type 2 diabetes mellitus
4. Liver fat ≥ 10% at screening as determined by the reading of the central MRI laboratory of
locally produced images
5. Patients must weigh at least 40 kg (88 lb) and no more than 150 kg (330 lb) to participate in
the study. Inclusion of patients with higher weights up to 200 kg (440 lbs) may occur if a
MRI scanner with a suitable table weight of 200 kg (440 lbs) is available. Patients must not
have ≥ 4.5 kg (10 lb) weight loss within the last 6 months prior to screening
6. Able to communicate well with the investigator, to understand and comply with the
requirements of the study
1. Written informed consent must be obtained before any assessment is performed
2. Male and female patients 18 years or older (at the time of the screening visit)
3. Presence of NASH as demonstrated by ONE of the following:
Histologic evidence of NASH based on liver biopsy obtained 2 years or less before
randomization with a diagnosis consistent with NASH, fibrosis level F1, F2 or F3, no
diagnosis of alternative chronic liver diseases AND
ALT ≥ 60 IU/L (males) or ≥ 40 IU/L (females)
OR
Phenotypic diagnosis of NASH based on presence of ALL THREE of the following:
o ALT ≥ 60 IU/L (males) or ≥ 40 IU/L (females) AND
o BMI ≥ 27 kg/m2
(in patients with a self-identified race other than Asian) or ≥ 23
kg/m2
(in patients with a self-identified Asian race) AND
o Diagnosis of Type 2 diabetes mellitus by having either:
- HbA1C ≥ 6.5% or
- Drug therapy for Type 2 diabetes mellitus
4. Liver fat ≥ 10% at screening as determined by the reading of the central MRI laboratory of
locally produced images
5. Patients must weigh at least 40 kg (88 lb) and no more than 150 kg (330 lb) to participate in
the study. Inclusion of patients with higher weights up to 200 kg (440 lbs) may occur if a
MRI scanner with a suitable table weight of 200 kg (440 lbs) is available. Patients must not
have ≥ 4.5 kg (10 lb) weight loss within the last 6 months prior to screening
6. Able to communicate well with the investigator, to understand and comply with the
requirements of the study
Exclusion Criteria
. Exclusion criteria:
1. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days,
whichever is longer
2. History of hypersensitivity to the study drug or its excipients or to drugs of similar chemical
classes
3. Previous exposure to obeticholic acid (OCA)
4. Patients taking medications prohibited by the protocol. See Section 5.5.8 for further details
5. Patients taking the following medicines must be on the same dose for 3 months before
randomization: anti-diabetic medications, insulin (if ≥ 25% change in dose), 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
6. History of treated or untreated malignancy of any organ system, other than localized basal cell
carcinoma of the skin or treated cervical intraepithelial neoplasia, within the past 5 years,
regardless of whether there is evidence of local recurrence or metastases
7. Pregnant or nursing (lactating) women
8. Women of child-bearing potential, defined as all women physiologically capable of becoming
pregnant, unless they are using highly effective methods of contraception during dosing and
for 5 days (= 5 times the terminal half-life of LJN452) after stopping of study treatment.
Highly effective contraception methods include:
Total abstinence (when this is in line with the preferred and usual lifestyle of the patient).
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods)
and withdrawal are not acceptable methods of contraception
Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy, total hysterectomy or tubal ligation) at least six weeks before taking study
treatment. In case of oophorectomy alone, the sterile reproductive status of the woman
must have been confirmed by follow up hormone level assessment
Male sterilization (at least 6 months prior to screening). For female patients on the study,
the vasectomized male partner should be the sole partner for that patient
Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS)
or other forms of hormonal contraception that have comparable efficacy (failure rate
<1%), for example hormone vaginal ring or transdermal hormone contraception
In case of use of oral contraception women should have been stable on the same pill for a
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 12
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy
(with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In
the case of oophorectomy alone, only when the reproductive status of the woman has been
confirmed by follow up hormone level assessment is she considered not of child bearing
potential.
9. Sexually active males must use a condom during intercourse while taking study medication
and for 5 days after stopping study medication and should not father a child in this period. A
condom is required to be used also by vasectomized men in order to prevent delivery of the
drug via seminal fluid
10. Current or history of significant alcohol consumption for a period of more than 3 consecutive
months within 1 year prior to screening (significant alcohol consumption is defined as more
than 20 g/day in females and more than 30 g/day in males, on average) and/or a score on the
AUDIT questionnaire ≥8
11. Inability to reliably quantify alcohol consumption based upon local study physician judgment
12. History or evidence of ongoing drug abuse, within the last 6 months prior to randomization.
Marijuana use is not allowed if it is determined to be medically inappropriate by the
investigator
13. Prior or planned (during the study period) bariatric surgery (eg, gastroplasty, roux-en-Y
gastric bypass)
14. Uncontrolled diabetes defined as HbAlc ≥ 9.5% within 60 days prior to enrollment
15. Presence of cirrhosis on liver biopsy or clinical diagnosis
16. Platelet count < 120 ×109/L
17. Clinical evidence of hepatic decompensation or severe liver impairment as defined by the
presence of any of the following abnormalities:
Serum albumin < 32 g/L
INR > 1.3
Direct bilirubin > 13 mg/L
ALT or AST > 5 × ULN
Alkaline phosphatase > 3 × ULN
History of esophageal varices, ascites or hepatic encephalopathy
Splenomegaly
18. Previous diagnosis of other forms of chronic liver disease:
Hepatitis B as defined by presence of hepatitis B surface antigen (HBsAg)
Hepatitis C as defined by presence of hepatitis C virus (HCV) RNA or positive hepatitis
C antibody (anti-HCV)
Evidence of ongoing autoimmune liver disease as defined by compatible liver histology
Primary biliary cholangitis as defined by the presence of at least 2 of these criteria
o Biochemical evidence of cholestasis based mainly on alkaline phosphatase elevation
o Presence of anti-mitochondrial antibodies (AMA)
o Histologic evidence of nonsuppurative destructive cholangitis and destruction of
interlobular bile ducts
Primary sclerosing cholangitis
Wilson's disease as defined by ceruloplasmin below the limits of normal and compatible
liver histology
Alpha-1-antitrypsin (A1AT) deficiency as defined by diagnostic features in liver
histology (confirmed by alpha-1 antitrypsin level less than normal; exclusion at the
discretion of the study physician)
History of hemochromatosis or iron overload as defined by presence of 3+ or 4+ stainable
iron on liver biopsy or iron saturation levels interpreted as hemochromatosis.
Drug-induced liver disease as defined on the basis of typical exposure and history
Known bile duct obstruction
Suspected or proven liver cancer
Suspected or confirmed Gilbert's syndrome
Any other type of liver disease other than NASH
19. Calculated eGFR less than 60 mL/min (using the MDRD formula)
20. History of biliary diversion or cholecystectomy
21. History of liver transplantation or current placement on a liver transplant list
22. Known positivity for Human Immunodeficiency Virus (HIV) infection
23. Active substance abuse including inhaled or injection drugs in the year prior to screening
24. Any other condition which, in the opinion of the investigator, would impede compliance or
hinder completion of the study
25. Chronic (> 3 months) use of excessive doses of Nonsteroidal Anti-inflammatory Drugs
(NSAIDs) as evaluated by investigator
26. Use of GLP-1 agonists such as liraglutide, exenatide , lixisenatide, albiglutide or dulaglutide
27. History or current diagnosis of ECG abnormalities indicating significant risk of safety for
patients participating in the study such as:
Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular
tachycardia, and clinically significant second or third degree AV block without a
pacemaker
History of familial long QT syndrome or known family history of Torsades de Pointes
28. Patients with contraindications to MRI imaging, including:
Brain aneurysm clip
Implanted neural stimulator
Implanted cardiac pacemaker or defibrillator, or presence of intracardiac wires
Prosthetic heart valves
Cochlear implant
Ocular foreign bodies that might be ferromagnetic (e.g., metal shavings)
Other implanted medical devices (e.g., insulin pumps)
Metal shrapnel or bullets still in the body
Severe claustrophobia
Tattoos (as determined by the Investigator and Imager)
Weight in excess of MRI machine capacity
29. History of inflammatory bowel disease
30. Previous exposure to LJN452
ALT and eGFR values must always fall inside the allowable range as listed in the inclusion
and exclusion criteria. For other laboratory values, provided patients meet all other eligibility
criteria, patients with a single lab value outside of the allowable range may be considered
eligible for enrolment, as long as that abnormal lab value is within 10% of the allowable value.
1. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days,
whichever is longer
2. History of hypersensitivity to the study drug or its excipients or to drugs of similar chemical
classes
3. Previous exposure to obeticholic acid (OCA)
4. Patients taking medications prohibited by the protocol. See Section 5.5.8 for further details
5. Patients taking the following medicines must be on the same dose for 3 months before
randomization: anti-diabetic medications, insulin (if ≥ 25% change in dose), 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
6. History of treated or untreated malignancy of any organ system, other than localized basal cell
carcinoma of the skin or treated cervical intraepithelial neoplasia, within the past 5 years,
regardless of whether there is evidence of local recurrence or metastases
7. Pregnant or nursing (lactating) women
8. Women of child-bearing potential, defined as all women physiologically capable of becoming
pregnant, unless they are using highly effective methods of contraception during dosing and
for 5 days (= 5 times the terminal half-life of LJN452) after stopping of study treatment.
Highly effective contraception methods include:
Total abstinence (when this is in line with the preferred and usual lifestyle of the patient).
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods)
and withdrawal are not acceptable methods of contraception
Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy, total hysterectomy or tubal ligation) at least six weeks before taking study
treatment. In case of oophorectomy alone, the sterile reproductive status of the woman
must have been confirmed by follow up hormone level assessment
Male sterilization (at least 6 months prior to screening). For female patients on the study,
the vasectomized male partner should be the sole partner for that patient
Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS)
or other forms of hormonal contraception that have comparable efficacy (failure rate
<1%), for example hormone vaginal ring or transdermal hormone contraception
In case of use of oral contraception women should have been stable on the same pill for a
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 12
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy
(with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In
the case of oophorectomy alone, only when the reproductive status of the woman has been
confirmed by follow up hormone level assessment is she considered not of child bearing
potential.
9. Sexually active males must use a condom during intercourse while taking study medication
and for 5 days after stopping study medication and should not father a child in this period. A
condom is required to be used also by vasectomized men in order to prevent delivery of the
drug via seminal fluid
10. Current or history of significant alcohol consumption for a period of more than 3 consecutive
months within 1 year prior to screening (significant alcohol consumption is defined as more
than 20 g/day in females and more than 30 g/day in males, on average) and/or a score on the
AUDIT questionnaire ≥8
11. Inability to reliably quantify alcohol consumption based upon local study physician judgment
12. History or evidence of ongoing drug abuse, within the last 6 months prior to randomization.
Marijuana use is not allowed if it is determined to be medically inappropriate by the
investigator
13. Prior or planned (during the study period) bariatric surgery (eg, gastroplasty, roux-en-Y
gastric bypass)
14. Uncontrolled diabetes defined as HbAlc ≥ 9.5% within 60 days prior to enrollment
15. Presence of cirrhosis on liver biopsy or clinical diagnosis
16. Platelet count < 120 ×109/L
17. Clinical evidence of hepatic decompensation or severe liver impairment as defined by the
presence of any of the following abnormalities:
Serum albumin < 32 g/L
INR > 1.3
Direct bilirubin > 13 mg/L
ALT or AST > 5 × ULN
Alkaline phosphatase > 3 × ULN
History of esophageal varices, ascites or hepatic encephalopathy
Splenomegaly
18. Previous diagnosis of other forms of chronic liver disease:
Hepatitis B as defined by presence of hepatitis B surface antigen (HBsAg)
Hepatitis C as defined by presence of hepatitis C virus (HCV) RNA or positive hepatitis
C antibody (anti-HCV)
Evidence of ongoing autoimmune liver disease as defined by compatible liver histology
Primary biliary cholangitis as defined by the presence of at least 2 of these criteria
o Biochemical evidence of cholestasis based mainly on alkaline phosphatase elevation
o Presence of anti-mitochondrial antibodies (AMA)
o Histologic evidence of nonsuppurative destructive cholangitis and destruction of
interlobular bile ducts
Primary sclerosing cholangitis
Wilson's disease as defined by ceruloplasmin below the limits of normal and compatible
liver histology
Alpha-1-antitrypsin (A1AT) deficiency as defined by diagnostic features in liver
histology (confirmed by alpha-1 antitrypsin level less than normal; exclusion at the
discretion of the study physician)
History of hemochromatosis or iron overload as defined by presence of 3+ or 4+ stainable
iron on liver biopsy or iron saturation levels interpreted as hemochromatosis.
Drug-induced liver disease as defined on the basis of typical exposure and history
Known bile duct obstruction
Suspected or proven liver cancer
Suspected or confirmed Gilbert's syndrome
Any other type of liver disease other than NASH
19. Calculated eGFR less than 60 mL/min (using the MDRD formula)
20. History of biliary diversion or cholecystectomy
21. History of liver transplantation or current placement on a liver transplant list
22. Known positivity for Human Immunodeficiency Virus (HIV) infection
23. Active substance abuse including inhaled or injection drugs in the year prior to screening
24. Any other condition which, in the opinion of the investigator, would impede compliance or
hinder completion of the study
25. Chronic (> 3 months) use of excessive doses of Nonsteroidal Anti-inflammatory Drugs
(NSAIDs) as evaluated by investigator
26. Use of GLP-1 agonists such as liraglutide, exenatide , lixisenatide, albiglutide or dulaglutide
27. History or current diagnosis of ECG abnormalities indicating significant risk of safety for
patients participating in the study such as:
Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular
tachycardia, and clinically significant second or third degree AV block without a
pacemaker
History of familial long QT syndrome or known family history of Torsades de Pointes
28. Patients with contraindications to MRI imaging, including:
Brain aneurysm clip
Implanted neural stimulator
Implanted cardiac pacemaker or defibrillator, or presence of intracardiac wires
Prosthetic heart valves
Cochlear implant
Ocular foreign bodies that might be ferromagnetic (e.g., metal shavings)
Other implanted medical devices (e.g., insulin pumps)
Metal shrapnel or bullets still in the body
Severe claustrophobia
Tattoos (as determined by the Investigator and Imager)
Weight in excess of MRI machine capacity
29. History of inflammatory bowel disease
30. Previous exposure to LJN452
ALT and eGFR values must always fall inside the allowable range as listed in the inclusion
and exclusion criteria. For other laboratory values, provided patients meet all other eligibility
criteria, patients with a single lab value outside of the allowable range may be considered
eligible for enrolment, as long as that abnormal lab value is within 10% of the allowable value.
The Estimated Number of Participants
-
Taiwan
50 participants
-
Global
345 participants
