Efficacy and Safety Study of Cenicriviroc for the Treatment of Nonalcoholic Steatohepatitis (NASH) in Adult Participants With Liver Fibrosis (CENTAUR)
Primary Purpose
Nonalcoholic Steatohepatitis
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Cenicriviroc
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Nonalcoholic Steatohepatitis
Eligibility Criteria
Inclusion Criteria:
- Adult participants aged between 18-75
- Histological evidence of NASH, based on biopsy, with a Nonalcoholic fatty liver disease Activity Score (NAS) of >= 4 with at least 1 in each component of NAS
- Histological evidence of liver fibrosis defined as NASH Clinical Research Network (CRN) System Stage 1 to 3
Meeting any of the 3 major criteria (a, b, c):
- Documented evidence of type 2 diabetes mellitus
High body mass index (> 25 kg/m^2) with at least one of the following criteria of metabolic syndrome, as defined by the National Cholesterol Education Program:
- Central obesity: waist circumference ≥ 102 cm or 40 inches (male), ≥ 88 cm or 35 inches (female)
- Dyslipidemia: Triglycerides ≥ 1.7 mmol/L (150 mg/dL)
- Dyslipidemia: High-density lipoprotein (HDL)-cholesterol < 40 mg/dL (male), < 50 mg/dL (female)
- Blood pressure ≥ 130/85 mmHg (or currently being treated for hypertension)
- Fasting plasma glucose ≥ 6.1 mmol/L (110 mg/dL)
- Bridging fibrosis (NASH CRN Stage 3) and/or definite NASH (NAS ≥ 5)
- Agree to have one liver biopsy at Screening, one at Year 1, and one at the end of study treatment (Year 2)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 × upper limit of normal (ULN)
Exclusion Criteria:
- Hepatitis B surface Antigen (HBsAg) positive
Hepatitis C antibody (HCVAb) positive with the following 2 exceptions:
- Participants previously treated for viral hepatitis C with at least a 1-year period since documented sustained virologic response at Week 12 (post-treatment) may be eligible if all other eligibility criteria are met
- Participants with presence of hepatitis C antibody but negative hepatitis C virus ribonucleic acid RNA without treatment (i.e., spontaneous clearance) may be eligible if all other eligibility criteria are met
- Prior or planned liver transplantation
- Other known causes of chronic liver disease, including alcoholic liver disease
- History of cirrhosis and/or hepatic decompensation including ascites, hepatic encephalopathy or variceal bleeding
- Alcohol consumption greater than 21 units/week for males or 14 units/week for females (one unit of alcohol is ½ pint of beer [285 mL], 1 glass of spirits [25 mL] or 1 glass of wine [125 mL])
- Human immunodeficiency virus (HIV)-1 or HIV-2 infection
- Weight reduction through bariatric surgery in the past 5 years or planned during the conduct of the study (including gastric banding)
- Females who are pregnant or breastfeeding
- Any other clinically significant disorders or prior therapy that, in the opinion of the investigator, would make the participant unsuitable for the study or unable to comply with the dosing and protocol requirements.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Placebo Comparator
Arm Label
Cenicriviroc (CVC) 150mg/CVC 150 mg
Placebo/CVC 150 mg
Placebo/Placebo
Arm Description
CVC 150 mg tablet in Years 1 and 2.
Placebo-matching CVC tablet in Year 1 then CVC 150 mg tablet in Year 2.
Placebo-matching cenicriviroc (CVC) tablet in Years 1 and 2.
Outcomes
Primary Outcome Measures
Number of Participant With Hepatic Histological Improvement in NAS by ≥ 2 Points With at Least 1-Point Reduction in Either Lobular Inflammation or Hepatocellular Ballooning and no Concurrent Worsening of Fibrosis at Year 1
Hepatic histological improvement in Nonalcoholic Fatty Liver Disease Activity Score (NAS) at Year 1 was defined as a decrease (improvement) in NAS by ≥ 2 with at least a 1-point reduction in either lobular inflammation or hepatocellular ballooning and with no concurrent worsening of fibrosis stage. The NAS was derived as the unweighted sum of steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocellular ballooning (0 to 2) scores. The NAS ranges from 0-8 with the higher score indicating more aggressive disease. Evaluation of fibrosis stage was based on the nonalcoholic steatohepatitis clinical research network (NASH CRN) fibrosis staging system, which was scaled from 0 to 4 stages where, 0=None to 4=Cirrhosis. Worsening of fibrosis stage was defined as progression of NASH CRN fibrosis stage.
Secondary Outcome Measures
Number of Participants With Complete Resolution of Steatohepatitis With no Concurrent Worsening of Fibrosis Stage and Improvement in Fibrosis by at Least 1 Stage (NASH CRN System) and no Worsening of Steatohepatitis at Year 1
Complete resolution of steatohepatitis was defined as histopathologic interpretation of no fatty liver disease, or simple or isolated steatosis with no steatohepatitis. As per NASH CRN system, no worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade. The evaluation of fibrosis stage associated with NASH was based on the NASH CRN fibrosis staging system which was scaled from 0 to 4 stages where, 0=None to 4=Cirrhosis.
Number of Participants With Complete Resolution of Steatohepatitis With no Concurrent Worsening of Fibrosis Stage and Improvement in Fibrosis by at Least 1 Stage (NASH CRN System) and no Worsening of Steatohepatitis at Year 2
Complete resolution of steatohepatitis was defined as histopathologic interpretation of no fatty liver disease, or simple or isolated steatosis with no steatohepatitis. As per NASH CRN system, no worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade. The evaluation of fibrosis stage associated with NASH was based on the NASH CRN fibrosis staging system which was scaled from 0 to 4 stages where, 0=None to 4=Cirrhosis.
Number of Participants With Complete Resolution of Steatohepatitis With no Concurrent Worsening of Fibrosis Stage at Year 1
Complete resolution of steatohepatitis was defined as histopathologic interpretation of no fatty liver disease, or simple or isolated steatosis with no steatohepatitis. As per NASH CRN system, no worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade. The evaluation of fibrosis stage associated with NASH was based on the NASH CRN fibrosis staging system which was scaled from 0 to 4 stages where, 0=None to 4=Cirrhosis.
Number of Participants With Complete Resolution of Steatohepatitis With no Concurrent Worsening of Fibrosis Stage at Year 2
Complete resolution of steatohepatitis was defined as histopathologic interpretation of no fatty liver disease, or simple or isolated steatosis with no steatohepatitis. As per NASH CRN system, no worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade. The evaluation of fibrosis stage associated with NASH was based on the NASH CRN fibrosis staging system which was scaled from 0 to 4 stages where, 0=None to 4=Cirrhosis.
Number of Participants With Improvement in Fibrosis by at Least 1 Stage (NASH CRN System) and no Worsening of Steatohepatitis at Year 1
The evaluation of fibrosis stage associated with NASH was based on the NASH CRN Fibrosis Staging System which was scaled from 0 to 4 stages where, 0=None to 4=Cirrhosis. As per NASH CRN system, no worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade.
Number of Participants With Improvement in Fibrosis by at Least 1 Stage (NASH CRN System) and no Worsening of Steatohepatitis at Year 2
The evaluation of fibrosis stage associated with NASH was based on the NASH CRN Fibrosis Staging System which was scaled from 0 to 4 stages where, 0=None to 4=Cirrhosis. As per NASH CRN system, no worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade.
Number of Participants With Deaths, Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), TEAEs Leading Study Drug to Discontinuation
A TEAE was defined as any adverse event that started or worsened on or after the start of the study medication and up to 30 days after the discontinuation of the study medication. An SAE was defined as any untoward medical occurrence that, at any dose, results in death, was life threatening, requires hospitalization or results in prolongation of existing hospitalization, results in disability/incapacity, or was a congenital anomaly/birth defect.
Number of Participants With Clinically Significant Changes in Vital Signs
Vital signs included blood pressure, temperature, heart rate, and respiration rate. Vital signs were reviewed by the Investigator for clinically significant changes.
Number of Participants With Clinical Laboratory Abnormalities
Grade 3-4 abnormal clinical laboratory values that occurred in ≥2% participants were reported. Criteria used for various parameters was:Fasting glucose Grade3:>250 - 500 mg/dL and Grade4: >500 mg/dL; Alanine aminotransferase(ALT)Grade3:>5.0 - 20.0 ×Upper Limit of Normal(ULN)and Grade4:>20.0 ×ULN; Aspartate aminotransferase(AST)Grade3: >5.0 - 20.0 ×ULN and Grade4: >20.0 ×ULN; Activated partial thromboplastin(APT)/Partial thromboplastin time(PTT)Grade3: >2.5×ULN; Triglycerides Grade3 >500 - 1000 mg/dL and Grade4: >1000 mg/dL; Gamma-glutamyl transferase(GGT)Grade3: >5.0 - 20.0 ×ULN and Grade4: >20.0 ×ULN; Creatine kinase Grade 3: >5.0 - 10.0 ×ULN and Grade4: >10.0 ×ULN; Uric acid Grade3:(ULN - 10 mg/dL; ULN - 0.59 mmol/L) and Grade4: >10 mg/dL; Amylase Grade3: >2.0 - 5.0 ×ULN and Grade4: >5.0 ×ULN; Lipase Grade3: >2.0 - 5.0 xULN and Grade4: >5.0 xULN; Phosphorus Grade3: <2.0 - 1.0 mg/dL and Grade4: <1.0 mg/dL and Absolute neutrophil Grade3: <1.0 - 0.5 × 109/L and Grade4: <0.5 × 109/L.
Number of Participants With Clinically Abnormal in Electrocardiogram (ECG) Findings
A 12-lead ECG was performed. ECG results were reviewed by the Investigator for clinically notable abnormalities.
Number of Participants With Hepatic Histological Improvement in NAS at Year 2
Hepatic histological improvement in NAS at Year 2 was defined as a decrease (improvement) in NAS by ≥ 2 with at least a 1-point reduction in either lobular inflammation or hepatocellular ballooning and with no concurrent worsening of fibrosis stage. The NAS was derived as the unweighted sum of steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocellular ballooning (0 to 2) scores. The NAS ranges from 0-8 with the higher score indicating more aggressive disease.
Change From Baseline in the 3 Categorical Features of NAS (Steatosis, Lobular Inflammation, Hepatocellular Ballooning) at Year 1
NAS was calculated using the following 3 categorical features: steatosis which was scaled from 0-3 (steatosis score is defined as 0= <5%, 1= 5 - 33%, 2= >33 - 66%, and 3= >66%), lobular inflammation which was scaled from 0-3 (lobular inflammation score defined as 0= no foci, 1= < 2 foci/200x, 2= 2-4 foci/200x, and 3= > 4 foci/200x), and hepatocellular ballooning which was scaled from 0-2 (hepatocellular ballooning score is defined as 0=none, 1=few balloon cells, 2=many cells/prominent ballooning). A negative change from Baseline indicates improvement.
Change From Baseline in the 3 Categorical Features of NAS (Steatosis, Lobular Inflammation, Hepatocellular Ballooning) at Year 2
NAS was calculated using the following 3 categorical features: steatosis which was scaled from 0-3 (steatosis score is defined as 0= <5%, 1= 5 - 33%, 2= >33 - 66%, and 3= >66%), lobular inflammation which was scaled from 0-3 (lobular inflammation score defined as 0= no foci, 1= < 2 foci/200x, 2= 2-4 foci/200x, and 3= > 4 foci/200x), and hepatocellular ballooning which was scaled from 0-2 (hepatocellular ballooning score is defined as 0=none, 1=few balloon cells, 2=many cells/prominent ballooning). A negative change from Baseline indicates improvement.
Number of Participants With Hepatic Histological Improvement With a Minimum 2-Point Improvement in NAS With at Least a 1-Point Improvement in More Than 1 Categorical Features of NAS and no Concurrent Worsening of Fibrosis Stage at Year 1
Hepatic histological improvement in NAS was defined as a decrease (improvement) in NAS by ≥ 2 with at least a 1-point reduction in either steatosis, lobular inflammation or hepatocellular ballooning and with no concurrent worsening of fibrosis stage. The NAS was derived as the unweighted sum of steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocellular ballooning (0 to 2) scores. The NAS ranges from 0-8 with the higher score indicating more aggressive disease. Worsening was defined as progression of NASH CRN fibrosis stage.
Number of Participants With Hepatic Histological Improvement With a Minimum 2-Point Improvement in NAS With at Least a 1-point Improvement in More Than 1 Categorical Features of NAS and no Concurrent Worsening of Fibrosis Stage at Year 2
Hepatic histological improvement in NAS was defined as a decrease (improvement) in NAS by ≥ 2 with at least a 1-point reduction in either steatosis, lobular inflammation or hepatocellular ballooning and with no concurrent worsening of fibrosis stage. The NAS was derived as the unweighted sum of steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocellular ballooning (0 to 2) scores. The NAS ranges from 0-8 with the higher score indicating more aggressive disease. Worsening was defined as progression of NASH CRN fibrosis stage.
Number of Participants With Resolution of NASH Using a Modified Definition Based on Categorical Features of NAS and no Concurrent Worsening of Fibrosis Stage at Year 1
Resolution of NASH was defined as having no hepatocellular ballooning (grade 0) and minimal to no lobular inflammation (grade 1 or 0) with no concurrent worsening of fibrosis stage (worsening defined as progression of NASH CRN fibrosis stage).
Number of Participants With Resolution of NASH Using a Modified Definition Based on Categorical Features of NAS and no Concurrent Worsening of Fibrosis Stage at Year 2
Resolution of NASH was defined as having no hepatocellular ballooning (grade 0) and minimal to no lobular inflammation (grade 1 or 0) with no concurrent worsening of fibrosis stage (worsening defined as progression of NASH CRN fibrosis stage).
Change From Baseline in Morphometric Quantitative Collagen on Liver Biopsy at Year 1
The morphometric quantitative collagen on liver biopsy was determined as percent collagen area (PCA) using Sirius red stain on liver biopsy at Year 1. A negative change from Baseline indicates improvement.
Change From Baseline in Morphometric Quantitative Collagen on Liver Biopsy at Year 2
The morphometric quantitative collagen on liver biopsy was determined as percent collagen area (PCA) using Sirius red stain on liver biopsy at Year 2. A negative change from Baseline indicates improvement.
Change From Baseline in Hepatic Tissue Fibrogenic Protein Alpha-Smooth Muscle Actin (α-SMA) at Year 1
The hepatic tissue fibrogenic protein α-SMA level was determined as percent α-SMA + area using α-SMA stain on liver biopsy at Year 1. A positive change from Baseline indicates worsening.
Change From Baseline in Hepatic Tissue Fibrogenic Protein Alpha-Smooth Muscle Actin (α-SMA) at Year 2
The hepatic tissue fibrogenic protein α-SMA level was determined as percent α-SMA + area using α-SMA stain on liver biopsy at Year 2. A positive change from Baseline indicates worsening.
Change From Baseline in Morphometric Quantitative Fat Content on Liver Biopsy at Year 1
The morphometric quantitative fat content was done to find out the amount of fat accumulated in the liver. A liver biopsy was performed to determine percent fat area, at Year 1. A negative change from Baseline indicates improvement.
Change From Baseline in Morphometric Quantitative Fat Content on Liver Biopsy at Year 2
The morphometric quantitative fat content was done to find out the amount of fat accumulated in the liver. A liver biopsy was performed to determine percent fat area, at Year 2. A negative change from Baseline indicates improvement.
Change From Baseline in Histologic Fibrosis Stage (NASH CRN System and Ishak Scale Score) at Year 1
The participant's histologic fibrosis stage was determined using the NASH CRN system and Ishak scale score assessment at Year 1. The evaluation of fibrosis stage associated with NASH was based on the NASH CRN Fibrosis Staging System which was scaled from 0 to 4 where, 0=None to 4=Cirrhosis. The histologic fibrosis stage based on the Ishak assessment was divided into 1 to 6 stages. Fibrosis was staged with the Ishak scale (ranging from 0=No fibrosis to 6=Cirrhosis). A positive change from Baseline indicates worsening.
Change From Baseline in Histologic Fibrosis Stage (NASH CRN System and Ishak Scale Score) at Year 2
The participant's histologic fibrosis stage was determined using the NASH CRN system and Ishak scale score assessment at Year 1. The evaluation of fibrosis stage associated with NASH was based on the NASH CRN Fibrosis Staging System which was scaled from 0 to 4 where, 0=None to 4=Cirrhosis. The histologic fibrosis stage based on the Ishak assessment was divided into 1 to 6 stages. Fibrosis was staged with the Ishak scale (ranging from 0=No fibrosis to 6=Cirrhosis). A negative change from Baseline indicates improvement.
Change From Baseline in Portal Inflammation Grade on Liver Biopsy at Year 1
Portal inflammation on liver biopsy was graded from 0 to 4 where 0= None, 1= Mild, 2= Moderate, and 3= Marked. A positive change from Baseline indicates worsening.
Change From Baseline in Portal Inflammation Grade on Liver Biopsy at Year 2
Portal inflammation on liver biopsy was graded from 0 to 4 where 0= None, 1= Mild, 2= Moderate, and 3= Marked. A positive change from Baseline indicates worsening.
Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Aspartate Aminotransferase to Platelet Count Ratio Index (APRI) at Months 3, 6 and 12
APRI is the ratio of aspartate aminotransferase (AST) to platelet count. It is calculated using formula, APRI = (AST level [/ULN] / platelet counts [10^9/L]) * 100. An APRI index of <=0.50 indicated the absence of significant fibrosis and an index of > 1.50 indicated the presence of significant fibrosis. A negative change from Baseline indicates decreased fibrosis.
Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Aspartate Aminotransferase to Platelet Count Ratio Index (APRI) at Months 15, 18 and 24
APRI is the ratio of aspartate aminotransferase (AST) to platelet count. It is calculated using formula, APRI = (AST level [/ULN] / platelet counts [10^9/L]) * 100. An APRI index of <=0.50 indicated the absence of significant fibrosis and an index of > 1.50 indicated the presence of significant fibrosis. A negative change from Baseline indicates decreased fibrosis.
Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Fibrosis-4 (FIB-4) at Months 3, 6 and 12
Fibrosis-4 is the ratio of age in years and aminotransferase to platelet count. It is a non-invasive hepatic fibrosis index score combining standard biochemical values, platelets, alanine aminotransferase (ALT), AST and age that is calculated using formula: FIB-4 = (Age [years] x AST [U/L]) / (platelets [10^9/L] x (square root of ALT [U/L])). A FIB-4 index of < 1.45 indicated no or moderate fibrosis and an index of > 3.25 indicated extensive fibrosis/cirrhosis. A positive change from Baseline indicates increased fibrosis.
Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Fibrosis-4 (FIB-4) at Months 15, 18 and 24
Fibrosis-4 is the ratio of age in years and aminotransferase to platelet count. It is a non-invasive hepatic fibrosis index score combining standard biochemical values, platelets, alanine aminotransferase (ALT), AST and age that is calculated using formula: FIB-4 = (Age [years] x AST [U/L]) / (platelets [10^9/L] x (square root of ALT [U/L])). A FIB-4 index of < 1.45 indicated no or moderate fibrosis and an index of > 3.25 indicated extensive fibrosis/cirrhosis. A positive change from Baseline indicates increased fibrosis.
Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Hyaluronic Acid at Months 6 and 12
Hyaluronic acid is a non-invasive hepatic fibrosis marker. A negative change from Baseline indicates decreased fibrosis.
Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Hyaluronic Acid at Months 18 and 24
Hyaluronic acid is a non-invasive hepatic fibrosis marker. A positive change from Baseline indicates increased fibrosis.
Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Nonalcoholic Fatty Liver Disease (NAFLD) Fibrosis Score (NFS) at Months 3, 6 and 12
NFS is calculated using formula: NFS = -1.675 + 0.037 * age (years) + 0.094 * Body mass index (BMI) (kg/m^2) + 1.13 * Impaired fasting glucose (IFG)/diabetes (yes = 1, no = 0) + 0.99 * Aspartate aminotransferase (AST)/ Alanine aminotransferase (ALT) ratio - 0.013 × platelet (*10^9/L) - 0.66 * albumin (g/dL). A negative change from Baseline indicates decreased fibrosis.
Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: NAFLD Fibrosis Score (NFS) at Months 15, 18 and 24
NFS is calculated using formula: NFS = -1.675 + 0.037 * age (years) + 0.094 * Body mass index (BMI) (kg/m^2) + 1.13 * Impaired fasting glucose (IFG)/diabetes (yes = 1, no = 0) + 0.99 * Aspartate aminotransferase (AST)/ Alanine aminotransferase (ALT) ratio - 0.013 × platelet (*10^9/L) - 0.66 * albumin (g/dL). A negative change from Baseline indicates decreased fibrosis.
Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score at Months 6 and 12
The markers of fibrosis assessed in this test comprised hyaluronic acid (CHA), tissue inhibitor of metalloproteinase (CTIMP1) and procollagen III N-terminal peptide (CP3NP); these are components of the extracellular matrix and basement sinusoidal membrane of the liver and are elevated during activation of the stellate cell. The ELF tests were performed on Centaur device and the composite score was calculated as follows: ELF score = 2.278 + 0.851 ln(CHA) + 0.751 ln (CP3NP) + 0.394 ln(CTIMP1). ELF score < 7.7: no to mild fibrosis; ≥ 7.7 - < 9.8: Moderate fibrosis; ≥ 9.8 - < 11.3: Severe fibrosis; ≥ 11.3: Cirrhosis. A negative change from Baseline indicates decreased fibrosis.
Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score at Months 18 and 24
The markers of fibrosis assessed in this test comprised hyaluronic acid (CHA), tissue inhibitor of metalloproteinase (CTIMP1) and procollagen III N-terminal peptide (CP3NP); these are components of the extracellular matrix and basement sinusoidal membrane of the liver and are elevated during activation of the stellate cell. The ELF tests were performed on Centaur device and the composite score was calculated as follows: ELF score = 2.278 + 0.851 ln(CHA) + 0.751 ln (CP3NP) + 0.394 ln(CTIMP1). ELF score < 7.7: no to mild fibrosis; ≥ 7.7 - < 9.8: Moderate fibrosis; ≥ 9.8 - < 11.3: Severe fibrosis; ≥ 11.3: Cirrhosis. A negative change from Baseline indicates decreased fibrosis.
Change From Baseline in Biomarkers of Hepatocyte Apoptosis: Caspase Cleaved (CK-18 [M-30]) Levels and Total M-65 (CK-18 [M-65]) Levels at Months 3, 6 and 12
Caspase-cleaved cytokeratin levels (CK18M30) and total M-65 (CK-18 [M-65]) were measured as biomarkers of hepatocyte apoptosis. A negative change from Baseline indicates decreased hepatocyte apoptosis.
Change From Baseline in Biomarkers of Hepatocyte Apoptosis: Caspase Cleaved (CK-18 [M-30]) Levels and Total M-65 (CK-18 [M-65]) Levels at Months 15, 18 and 24
Caspase-cleaved cytokeratin levels (CK18M30) and total M-65 (CK-18 [M-65]) were measured as biomarkers of hepatocyte apoptosis. A negative change from Baseline indicates decreased hepatocyte apoptosis.
Change From Baseline in Weight at Months 3, 6 and 12
A negative change from Baseline represents decreased weight.
Change From Baseline in Weight at Months 15, 18 and 24
A negative change from Baseline represents decreased weight.
Change From Baseline in Body Mass Index (BMI) at Months 3, 6 and 12
The body mass index is a value derived from the mass (weight in kgs) and height (in centimeters) of an individual and is calculated as the body mass divided by the square of the body height. A negative change from Baseline represents decreased BMI.
Change From Baseline in Body Mass Index (BMI) at Months 15, 18 and 24
The body mass index is a value derived from the mass (weight in kgs) and height (in centimeters) of an individual and is calculated as the body mass divided by the square of the body height. A negative change from Baseline represents decreased BMI.
Change From Baseline in Waist Circumference at Months 3, 6 and 12
A negative change from Baseline represents decreased in waist circumference.
Change From Baseline in Waist Circumference at Months 15, 18 and 24
A negative change from Baseline represents decreased in waist circumference.
Change From Baseline in Hip Circumference at Months 3, 6 and 12
A negative change from Baseline represents decreased hip circumference.
Change From Baseline in Hip Circumference at Months 15, 18 and 24
A negative change from Baseline represents decreased hip circumference.
Change From Baseline in Forearm Circumference at Months 3, 6 and 12
A negative change from Baseline represents decreased forearm circumference.
Change From Baseline in Forearm Circumference at Months 15, 18 and 24
A negative change from Baseline represents decreased forearm circumference.
Change From Baseline in Tricep Skinfold Thickness at Months 3, 6 and 12
A negative change from Baseline represents decreased Tricep Skinfold Thickness.
Change From Baseline in Tricep Skinfold Thickness at Months 15, 18 and 24
A negative change from Baseline represents decreased Tricep Skinfold Thickness.
Full Information
NCT ID
NCT02217475
First Posted
August 13, 2014
Last Updated
April 19, 2019
Sponsor
Tobira Therapeutics, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT02217475
Brief Title
Efficacy and Safety Study of Cenicriviroc for the Treatment of Nonalcoholic Steatohepatitis (NASH) in Adult Participants With Liver Fibrosis
Acronym
CENTAUR
Official Title
CENTAUR: Efficacy and Safety Study of Cenicriviroc for the Treatment of Nonalcoholic Steatohepatitis (NASH) in Adult Subjects With Liver Fibrosis
Study Type
Interventional
2. Study Status
Record Verification Date
March 2019
Overall Recruitment Status
Completed
Study Start Date
September 18, 2014 (Actual)
Primary Completion Date
June 30, 2016 (Actual)
Study Completion Date
June 22, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Tobira Therapeutics, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of this study is to determine whether cenicriviroc is effective and safe in the treatment of nonalcoholic steatohepatitis (NASH) in adult participants with liver fibrosis.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Nonalcoholic Steatohepatitis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
289 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cenicriviroc (CVC) 150mg/CVC 150 mg
Arm Type
Experimental
Arm Description
CVC 150 mg tablet in Years 1 and 2.
Arm Title
Placebo/CVC 150 mg
Arm Type
Experimental
Arm Description
Placebo-matching CVC tablet in Year 1 then CVC 150 mg tablet in Year 2.
Arm Title
Placebo/Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo-matching cenicriviroc (CVC) tablet in Years 1 and 2.
Intervention Type
Drug
Intervention Name(s)
Cenicriviroc
Other Intervention Name(s)
TBR-652
Intervention Description
CVC 150 mg, administered orally once daily and taken every morning with food.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo administered orally once daily and taken every morning with food.
Primary Outcome Measure Information:
Title
Number of Participant With Hepatic Histological Improvement in NAS by ≥ 2 Points With at Least 1-Point Reduction in Either Lobular Inflammation or Hepatocellular Ballooning and no Concurrent Worsening of Fibrosis at Year 1
Description
Hepatic histological improvement in Nonalcoholic Fatty Liver Disease Activity Score (NAS) at Year 1 was defined as a decrease (improvement) in NAS by ≥ 2 with at least a 1-point reduction in either lobular inflammation or hepatocellular ballooning and with no concurrent worsening of fibrosis stage. The NAS was derived as the unweighted sum of steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocellular ballooning (0 to 2) scores. The NAS ranges from 0-8 with the higher score indicating more aggressive disease. Evaluation of fibrosis stage was based on the nonalcoholic steatohepatitis clinical research network (NASH CRN) fibrosis staging system, which was scaled from 0 to 4 stages where, 0=None to 4=Cirrhosis. Worsening of fibrosis stage was defined as progression of NASH CRN fibrosis stage.
Time Frame
Year 1
Secondary Outcome Measure Information:
Title
Number of Participants With Complete Resolution of Steatohepatitis With no Concurrent Worsening of Fibrosis Stage and Improvement in Fibrosis by at Least 1 Stage (NASH CRN System) and no Worsening of Steatohepatitis at Year 1
Description
Complete resolution of steatohepatitis was defined as histopathologic interpretation of no fatty liver disease, or simple or isolated steatosis with no steatohepatitis. As per NASH CRN system, no worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade. The evaluation of fibrosis stage associated with NASH was based on the NASH CRN fibrosis staging system which was scaled from 0 to 4 stages where, 0=None to 4=Cirrhosis.
Time Frame
Year 1
Title
Number of Participants With Complete Resolution of Steatohepatitis With no Concurrent Worsening of Fibrosis Stage and Improvement in Fibrosis by at Least 1 Stage (NASH CRN System) and no Worsening of Steatohepatitis at Year 2
Description
Complete resolution of steatohepatitis was defined as histopathologic interpretation of no fatty liver disease, or simple or isolated steatosis with no steatohepatitis. As per NASH CRN system, no worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade. The evaluation of fibrosis stage associated with NASH was based on the NASH CRN fibrosis staging system which was scaled from 0 to 4 stages where, 0=None to 4=Cirrhosis.
Time Frame
Year 2
Title
Number of Participants With Complete Resolution of Steatohepatitis With no Concurrent Worsening of Fibrosis Stage at Year 1
Description
Complete resolution of steatohepatitis was defined as histopathologic interpretation of no fatty liver disease, or simple or isolated steatosis with no steatohepatitis. As per NASH CRN system, no worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade. The evaluation of fibrosis stage associated with NASH was based on the NASH CRN fibrosis staging system which was scaled from 0 to 4 stages where, 0=None to 4=Cirrhosis.
Time Frame
Year 1
Title
Number of Participants With Complete Resolution of Steatohepatitis With no Concurrent Worsening of Fibrosis Stage at Year 2
Description
Complete resolution of steatohepatitis was defined as histopathologic interpretation of no fatty liver disease, or simple or isolated steatosis with no steatohepatitis. As per NASH CRN system, no worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade. The evaluation of fibrosis stage associated with NASH was based on the NASH CRN fibrosis staging system which was scaled from 0 to 4 stages where, 0=None to 4=Cirrhosis.
Time Frame
Year 2
Title
Number of Participants With Improvement in Fibrosis by at Least 1 Stage (NASH CRN System) and no Worsening of Steatohepatitis at Year 1
Description
The evaluation of fibrosis stage associated with NASH was based on the NASH CRN Fibrosis Staging System which was scaled from 0 to 4 stages where, 0=None to 4=Cirrhosis. As per NASH CRN system, no worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade.
Time Frame
Year 1
Title
Number of Participants With Improvement in Fibrosis by at Least 1 Stage (NASH CRN System) and no Worsening of Steatohepatitis at Year 2
Description
The evaluation of fibrosis stage associated with NASH was based on the NASH CRN Fibrosis Staging System which was scaled from 0 to 4 stages where, 0=None to 4=Cirrhosis. As per NASH CRN system, no worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade.
Time Frame
Year 2
Title
Number of Participants With Deaths, Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), TEAEs Leading Study Drug to Discontinuation
Description
A TEAE was defined as any adverse event that started or worsened on or after the start of the study medication and up to 30 days after the discontinuation of the study medication. An SAE was defined as any untoward medical occurrence that, at any dose, results in death, was life threatening, requires hospitalization or results in prolongation of existing hospitalization, results in disability/incapacity, or was a congenital anomaly/birth defect.
Time Frame
Years 1 and 2
Title
Number of Participants With Clinically Significant Changes in Vital Signs
Description
Vital signs included blood pressure, temperature, heart rate, and respiration rate. Vital signs were reviewed by the Investigator for clinically significant changes.
Time Frame
Years 1 and 2
Title
Number of Participants With Clinical Laboratory Abnormalities
Description
Grade 3-4 abnormal clinical laboratory values that occurred in ≥2% participants were reported. Criteria used for various parameters was:Fasting glucose Grade3:>250 - 500 mg/dL and Grade4: >500 mg/dL; Alanine aminotransferase(ALT)Grade3:>5.0 - 20.0 ×Upper Limit of Normal(ULN)and Grade4:>20.0 ×ULN; Aspartate aminotransferase(AST)Grade3: >5.0 - 20.0 ×ULN and Grade4: >20.0 ×ULN; Activated partial thromboplastin(APT)/Partial thromboplastin time(PTT)Grade3: >2.5×ULN; Triglycerides Grade3 >500 - 1000 mg/dL and Grade4: >1000 mg/dL; Gamma-glutamyl transferase(GGT)Grade3: >5.0 - 20.0 ×ULN and Grade4: >20.0 ×ULN; Creatine kinase Grade 3: >5.0 - 10.0 ×ULN and Grade4: >10.0 ×ULN; Uric acid Grade3:(ULN - 10 mg/dL; ULN - 0.59 mmol/L) and Grade4: >10 mg/dL; Amylase Grade3: >2.0 - 5.0 ×ULN and Grade4: >5.0 ×ULN; Lipase Grade3: >2.0 - 5.0 xULN and Grade4: >5.0 xULN; Phosphorus Grade3: <2.0 - 1.0 mg/dL and Grade4: <1.0 mg/dL and Absolute neutrophil Grade3: <1.0 - 0.5 × 109/L and Grade4: <0.5 × 109/L.
Time Frame
Years 1 and 2
Title
Number of Participants With Clinically Abnormal in Electrocardiogram (ECG) Findings
Description
A 12-lead ECG was performed. ECG results were reviewed by the Investigator for clinically notable abnormalities.
Time Frame
Years 1 and 2
Title
Number of Participants With Hepatic Histological Improvement in NAS at Year 2
Description
Hepatic histological improvement in NAS at Year 2 was defined as a decrease (improvement) in NAS by ≥ 2 with at least a 1-point reduction in either lobular inflammation or hepatocellular ballooning and with no concurrent worsening of fibrosis stage. The NAS was derived as the unweighted sum of steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocellular ballooning (0 to 2) scores. The NAS ranges from 0-8 with the higher score indicating more aggressive disease.
Time Frame
Year 2
Title
Change From Baseline in the 3 Categorical Features of NAS (Steatosis, Lobular Inflammation, Hepatocellular Ballooning) at Year 1
Description
NAS was calculated using the following 3 categorical features: steatosis which was scaled from 0-3 (steatosis score is defined as 0= <5%, 1= 5 - 33%, 2= >33 - 66%, and 3= >66%), lobular inflammation which was scaled from 0-3 (lobular inflammation score defined as 0= no foci, 1= < 2 foci/200x, 2= 2-4 foci/200x, and 3= > 4 foci/200x), and hepatocellular ballooning which was scaled from 0-2 (hepatocellular ballooning score is defined as 0=none, 1=few balloon cells, 2=many cells/prominent ballooning). A negative change from Baseline indicates improvement.
Time Frame
Year 1
Title
Change From Baseline in the 3 Categorical Features of NAS (Steatosis, Lobular Inflammation, Hepatocellular Ballooning) at Year 2
Description
NAS was calculated using the following 3 categorical features: steatosis which was scaled from 0-3 (steatosis score is defined as 0= <5%, 1= 5 - 33%, 2= >33 - 66%, and 3= >66%), lobular inflammation which was scaled from 0-3 (lobular inflammation score defined as 0= no foci, 1= < 2 foci/200x, 2= 2-4 foci/200x, and 3= > 4 foci/200x), and hepatocellular ballooning which was scaled from 0-2 (hepatocellular ballooning score is defined as 0=none, 1=few balloon cells, 2=many cells/prominent ballooning). A negative change from Baseline indicates improvement.
Time Frame
Year 2
Title
Number of Participants With Hepatic Histological Improvement With a Minimum 2-Point Improvement in NAS With at Least a 1-Point Improvement in More Than 1 Categorical Features of NAS and no Concurrent Worsening of Fibrosis Stage at Year 1
Description
Hepatic histological improvement in NAS was defined as a decrease (improvement) in NAS by ≥ 2 with at least a 1-point reduction in either steatosis, lobular inflammation or hepatocellular ballooning and with no concurrent worsening of fibrosis stage. The NAS was derived as the unweighted sum of steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocellular ballooning (0 to 2) scores. The NAS ranges from 0-8 with the higher score indicating more aggressive disease. Worsening was defined as progression of NASH CRN fibrosis stage.
Time Frame
Year 1
Title
Number of Participants With Hepatic Histological Improvement With a Minimum 2-Point Improvement in NAS With at Least a 1-point Improvement in More Than 1 Categorical Features of NAS and no Concurrent Worsening of Fibrosis Stage at Year 2
Description
Hepatic histological improvement in NAS was defined as a decrease (improvement) in NAS by ≥ 2 with at least a 1-point reduction in either steatosis, lobular inflammation or hepatocellular ballooning and with no concurrent worsening of fibrosis stage. The NAS was derived as the unweighted sum of steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocellular ballooning (0 to 2) scores. The NAS ranges from 0-8 with the higher score indicating more aggressive disease. Worsening was defined as progression of NASH CRN fibrosis stage.
Time Frame
Year 2
Title
Number of Participants With Resolution of NASH Using a Modified Definition Based on Categorical Features of NAS and no Concurrent Worsening of Fibrosis Stage at Year 1
Description
Resolution of NASH was defined as having no hepatocellular ballooning (grade 0) and minimal to no lobular inflammation (grade 1 or 0) with no concurrent worsening of fibrosis stage (worsening defined as progression of NASH CRN fibrosis stage).
Time Frame
Year 1
Title
Number of Participants With Resolution of NASH Using a Modified Definition Based on Categorical Features of NAS and no Concurrent Worsening of Fibrosis Stage at Year 2
Description
Resolution of NASH was defined as having no hepatocellular ballooning (grade 0) and minimal to no lobular inflammation (grade 1 or 0) with no concurrent worsening of fibrosis stage (worsening defined as progression of NASH CRN fibrosis stage).
Time Frame
Year 2
Title
Change From Baseline in Morphometric Quantitative Collagen on Liver Biopsy at Year 1
Description
The morphometric quantitative collagen on liver biopsy was determined as percent collagen area (PCA) using Sirius red stain on liver biopsy at Year 1. A negative change from Baseline indicates improvement.
Time Frame
Year 1
Title
Change From Baseline in Morphometric Quantitative Collagen on Liver Biopsy at Year 2
Description
The morphometric quantitative collagen on liver biopsy was determined as percent collagen area (PCA) using Sirius red stain on liver biopsy at Year 2. A negative change from Baseline indicates improvement.
Time Frame
Year 2
Title
Change From Baseline in Hepatic Tissue Fibrogenic Protein Alpha-Smooth Muscle Actin (α-SMA) at Year 1
Description
The hepatic tissue fibrogenic protein α-SMA level was determined as percent α-SMA + area using α-SMA stain on liver biopsy at Year 1. A positive change from Baseline indicates worsening.
Time Frame
Baseline (Day 1) to Year 1
Title
Change From Baseline in Hepatic Tissue Fibrogenic Protein Alpha-Smooth Muscle Actin (α-SMA) at Year 2
Description
The hepatic tissue fibrogenic protein α-SMA level was determined as percent α-SMA + area using α-SMA stain on liver biopsy at Year 2. A positive change from Baseline indicates worsening.
Time Frame
Baseline (Day 1) to Year 2
Title
Change From Baseline in Morphometric Quantitative Fat Content on Liver Biopsy at Year 1
Description
The morphometric quantitative fat content was done to find out the amount of fat accumulated in the liver. A liver biopsy was performed to determine percent fat area, at Year 1. A negative change from Baseline indicates improvement.
Time Frame
Year 1
Title
Change From Baseline in Morphometric Quantitative Fat Content on Liver Biopsy at Year 2
Description
The morphometric quantitative fat content was done to find out the amount of fat accumulated in the liver. A liver biopsy was performed to determine percent fat area, at Year 2. A negative change from Baseline indicates improvement.
Time Frame
Year 2
Title
Change From Baseline in Histologic Fibrosis Stage (NASH CRN System and Ishak Scale Score) at Year 1
Description
The participant's histologic fibrosis stage was determined using the NASH CRN system and Ishak scale score assessment at Year 1. The evaluation of fibrosis stage associated with NASH was based on the NASH CRN Fibrosis Staging System which was scaled from 0 to 4 where, 0=None to 4=Cirrhosis. The histologic fibrosis stage based on the Ishak assessment was divided into 1 to 6 stages. Fibrosis was staged with the Ishak scale (ranging from 0=No fibrosis to 6=Cirrhosis). A positive change from Baseline indicates worsening.
Time Frame
Baseline (Day 1) to Year 1
Title
Change From Baseline in Histologic Fibrosis Stage (NASH CRN System and Ishak Scale Score) at Year 2
Description
The participant's histologic fibrosis stage was determined using the NASH CRN system and Ishak scale score assessment at Year 1. The evaluation of fibrosis stage associated with NASH was based on the NASH CRN Fibrosis Staging System which was scaled from 0 to 4 where, 0=None to 4=Cirrhosis. The histologic fibrosis stage based on the Ishak assessment was divided into 1 to 6 stages. Fibrosis was staged with the Ishak scale (ranging from 0=No fibrosis to 6=Cirrhosis). A negative change from Baseline indicates improvement.
Time Frame
Baseline (Day 1) to Year 2
Title
Change From Baseline in Portal Inflammation Grade on Liver Biopsy at Year 1
Description
Portal inflammation on liver biopsy was graded from 0 to 4 where 0= None, 1= Mild, 2= Moderate, and 3= Marked. A positive change from Baseline indicates worsening.
Time Frame
Baseline (Day 1) to Year 1
Title
Change From Baseline in Portal Inflammation Grade on Liver Biopsy at Year 2
Description
Portal inflammation on liver biopsy was graded from 0 to 4 where 0= None, 1= Mild, 2= Moderate, and 3= Marked. A positive change from Baseline indicates worsening.
Time Frame
Baseline (Day 1) to Year 2
Title
Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Aspartate Aminotransferase to Platelet Count Ratio Index (APRI) at Months 3, 6 and 12
Description
APRI is the ratio of aspartate aminotransferase (AST) to platelet count. It is calculated using formula, APRI = (AST level [/ULN] / platelet counts [10^9/L]) * 100. An APRI index of <=0.50 indicated the absence of significant fibrosis and an index of > 1.50 indicated the presence of significant fibrosis. A negative change from Baseline indicates decreased fibrosis.
Time Frame
Baseline (Month 0) to Months 3, 6 and 12
Title
Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Aspartate Aminotransferase to Platelet Count Ratio Index (APRI) at Months 15, 18 and 24
Description
APRI is the ratio of aspartate aminotransferase (AST) to platelet count. It is calculated using formula, APRI = (AST level [/ULN] / platelet counts [10^9/L]) * 100. An APRI index of <=0.50 indicated the absence of significant fibrosis and an index of > 1.50 indicated the presence of significant fibrosis. A negative change from Baseline indicates decreased fibrosis.
Time Frame
Baseline (Month 0) to Months 15, 18 and 24
Title
Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Fibrosis-4 (FIB-4) at Months 3, 6 and 12
Description
Fibrosis-4 is the ratio of age in years and aminotransferase to platelet count. It is a non-invasive hepatic fibrosis index score combining standard biochemical values, platelets, alanine aminotransferase (ALT), AST and age that is calculated using formula: FIB-4 = (Age [years] x AST [U/L]) / (platelets [10^9/L] x (square root of ALT [U/L])). A FIB-4 index of < 1.45 indicated no or moderate fibrosis and an index of > 3.25 indicated extensive fibrosis/cirrhosis. A positive change from Baseline indicates increased fibrosis.
Time Frame
Baseline (Month 0) to Months 3, 6 and 12
Title
Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Fibrosis-4 (FIB-4) at Months 15, 18 and 24
Description
Fibrosis-4 is the ratio of age in years and aminotransferase to platelet count. It is a non-invasive hepatic fibrosis index score combining standard biochemical values, platelets, alanine aminotransferase (ALT), AST and age that is calculated using formula: FIB-4 = (Age [years] x AST [U/L]) / (platelets [10^9/L] x (square root of ALT [U/L])). A FIB-4 index of < 1.45 indicated no or moderate fibrosis and an index of > 3.25 indicated extensive fibrosis/cirrhosis. A positive change from Baseline indicates increased fibrosis.
Time Frame
Baseline (Month 0) to Months 15, 18 and 24
Title
Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Hyaluronic Acid at Months 6 and 12
Description
Hyaluronic acid is a non-invasive hepatic fibrosis marker. A negative change from Baseline indicates decreased fibrosis.
Time Frame
Baseline (Month 0) to Months 6 and 12
Title
Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Hyaluronic Acid at Months 18 and 24
Description
Hyaluronic acid is a non-invasive hepatic fibrosis marker. A positive change from Baseline indicates increased fibrosis.
Time Frame
Baseline (Month 0) to Months 18 and 24
Title
Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Nonalcoholic Fatty Liver Disease (NAFLD) Fibrosis Score (NFS) at Months 3, 6 and 12
Description
NFS is calculated using formula: NFS = -1.675 + 0.037 * age (years) + 0.094 * Body mass index (BMI) (kg/m^2) + 1.13 * Impaired fasting glucose (IFG)/diabetes (yes = 1, no = 0) + 0.99 * Aspartate aminotransferase (AST)/ Alanine aminotransferase (ALT) ratio - 0.013 × platelet (*10^9/L) - 0.66 * albumin (g/dL). A negative change from Baseline indicates decreased fibrosis.
Time Frame
Baseline (Month 0) to Months 3, 6 and 12
Title
Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: NAFLD Fibrosis Score (NFS) at Months 15, 18 and 24
Description
NFS is calculated using formula: NFS = -1.675 + 0.037 * age (years) + 0.094 * Body mass index (BMI) (kg/m^2) + 1.13 * Impaired fasting glucose (IFG)/diabetes (yes = 1, no = 0) + 0.99 * Aspartate aminotransferase (AST)/ Alanine aminotransferase (ALT) ratio - 0.013 × platelet (*10^9/L) - 0.66 * albumin (g/dL). A negative change from Baseline indicates decreased fibrosis.
Time Frame
Baseline (Month 0) to Months 15, 18 and 24
Title
Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score at Months 6 and 12
Description
The markers of fibrosis assessed in this test comprised hyaluronic acid (CHA), tissue inhibitor of metalloproteinase (CTIMP1) and procollagen III N-terminal peptide (CP3NP); these are components of the extracellular matrix and basement sinusoidal membrane of the liver and are elevated during activation of the stellate cell. The ELF tests were performed on Centaur device and the composite score was calculated as follows: ELF score = 2.278 + 0.851 ln(CHA) + 0.751 ln (CP3NP) + 0.394 ln(CTIMP1). ELF score < 7.7: no to mild fibrosis; ≥ 7.7 - < 9.8: Moderate fibrosis; ≥ 9.8 - < 11.3: Severe fibrosis; ≥ 11.3: Cirrhosis. A negative change from Baseline indicates decreased fibrosis.
Time Frame
Baseline (Month 0) to Months 6 and 12
Title
Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score at Months 18 and 24
Description
The markers of fibrosis assessed in this test comprised hyaluronic acid (CHA), tissue inhibitor of metalloproteinase (CTIMP1) and procollagen III N-terminal peptide (CP3NP); these are components of the extracellular matrix and basement sinusoidal membrane of the liver and are elevated during activation of the stellate cell. The ELF tests were performed on Centaur device and the composite score was calculated as follows: ELF score = 2.278 + 0.851 ln(CHA) + 0.751 ln (CP3NP) + 0.394 ln(CTIMP1). ELF score < 7.7: no to mild fibrosis; ≥ 7.7 - < 9.8: Moderate fibrosis; ≥ 9.8 - < 11.3: Severe fibrosis; ≥ 11.3: Cirrhosis. A negative change from Baseline indicates decreased fibrosis.
Time Frame
Baseline (Month 0) to Months 18 and 24
Title
Change From Baseline in Biomarkers of Hepatocyte Apoptosis: Caspase Cleaved (CK-18 [M-30]) Levels and Total M-65 (CK-18 [M-65]) Levels at Months 3, 6 and 12
Description
Caspase-cleaved cytokeratin levels (CK18M30) and total M-65 (CK-18 [M-65]) were measured as biomarkers of hepatocyte apoptosis. A negative change from Baseline indicates decreased hepatocyte apoptosis.
Time Frame
Baseline (Month 0) to Months 3, 6 and 12
Title
Change From Baseline in Biomarkers of Hepatocyte Apoptosis: Caspase Cleaved (CK-18 [M-30]) Levels and Total M-65 (CK-18 [M-65]) Levels at Months 15, 18 and 24
Description
Caspase-cleaved cytokeratin levels (CK18M30) and total M-65 (CK-18 [M-65]) were measured as biomarkers of hepatocyte apoptosis. A negative change from Baseline indicates decreased hepatocyte apoptosis.
Time Frame
Baseline (Month 0) to Months 15, 18 and 24
Title
Change From Baseline in Weight at Months 3, 6 and 12
Description
A negative change from Baseline represents decreased weight.
Time Frame
Baseline (Day 1) to Months 3, 6 and 12
Title
Change From Baseline in Weight at Months 15, 18 and 24
Description
A negative change from Baseline represents decreased weight.
Time Frame
Baseline (Day 1) to Months 15, 18 and 24
Title
Change From Baseline in Body Mass Index (BMI) at Months 3, 6 and 12
Description
The body mass index is a value derived from the mass (weight in kgs) and height (in centimeters) of an individual and is calculated as the body mass divided by the square of the body height. A negative change from Baseline represents decreased BMI.
Time Frame
Baseline (Day 1) to Months 3, 6 and 12
Title
Change From Baseline in Body Mass Index (BMI) at Months 15, 18 and 24
Description
The body mass index is a value derived from the mass (weight in kgs) and height (in centimeters) of an individual and is calculated as the body mass divided by the square of the body height. A negative change from Baseline represents decreased BMI.
Time Frame
Baseline (Day 1) to Months 15, 18 and 24
Title
Change From Baseline in Waist Circumference at Months 3, 6 and 12
Description
A negative change from Baseline represents decreased in waist circumference.
Time Frame
Baseline (Day 1) to Months 3, 6 and 12
Title
Change From Baseline in Waist Circumference at Months 15, 18 and 24
Description
A negative change from Baseline represents decreased in waist circumference.
Time Frame
Baseline (Day 1) to Months 15, 18 and 24
Title
Change From Baseline in Hip Circumference at Months 3, 6 and 12
Description
A negative change from Baseline represents decreased hip circumference.
Time Frame
Baseline (Day 1) to Months 3, 6 and 12
Title
Change From Baseline in Hip Circumference at Months 15, 18 and 24
Description
A negative change from Baseline represents decreased hip circumference.
Time Frame
Baseline (Day 1) to Months 15, 18 and 24
Title
Change From Baseline in Forearm Circumference at Months 3, 6 and 12
Description
A negative change from Baseline represents decreased forearm circumference.
Time Frame
Baseline (Day 1) to Months 3, 6 and 12
Title
Change From Baseline in Forearm Circumference at Months 15, 18 and 24
Description
A negative change from Baseline represents decreased forearm circumference.
Time Frame
Baseline (Day 1) to Months 15, 18 and 24
Title
Change From Baseline in Tricep Skinfold Thickness at Months 3, 6 and 12
Description
A negative change from Baseline represents decreased Tricep Skinfold Thickness.
Time Frame
Baseline (Day 1) to Months 3, 6 and 12
Title
Change From Baseline in Tricep Skinfold Thickness at Months 15, 18 and 24
Description
A negative change from Baseline represents decreased Tricep Skinfold Thickness.
Time Frame
Baseline (Day 1) to Months 15, 18 and 24
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Adult participants aged between 18-75
Histological evidence of NASH, based on biopsy, with a Nonalcoholic fatty liver disease Activity Score (NAS) of >= 4 with at least 1 in each component of NAS
Histological evidence of liver fibrosis defined as NASH Clinical Research Network (CRN) System Stage 1 to 3
Meeting any of the 3 major criteria (a, b, c):
Documented evidence of type 2 diabetes mellitus
High body mass index (> 25 kg/m^2) with at least one of the following criteria of metabolic syndrome, as defined by the National Cholesterol Education Program:
Central obesity: waist circumference ≥ 102 cm or 40 inches (male), ≥ 88 cm or 35 inches (female)
Dyslipidemia: Triglycerides ≥ 1.7 mmol/L (150 mg/dL)
Dyslipidemia: High-density lipoprotein (HDL)-cholesterol < 40 mg/dL (male), < 50 mg/dL (female)
Blood pressure ≥ 130/85 mmHg (or currently being treated for hypertension)
Fasting plasma glucose ≥ 6.1 mmol/L (110 mg/dL)
Bridging fibrosis (NASH CRN Stage 3) and/or definite NASH (NAS ≥ 5)
Agree to have one liver biopsy at Screening, one at Year 1, and one at the end of study treatment (Year 2)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 × upper limit of normal (ULN)
Exclusion Criteria:
Hepatitis B surface Antigen (HBsAg) positive
Hepatitis C antibody (HCVAb) positive with the following 2 exceptions:
Participants previously treated for viral hepatitis C with at least a 1-year period since documented sustained virologic response at Week 12 (post-treatment) may be eligible if all other eligibility criteria are met
Participants with presence of hepatitis C antibody but negative hepatitis C virus ribonucleic acid RNA without treatment (i.e., spontaneous clearance) may be eligible if all other eligibility criteria are met
Prior or planned liver transplantation
Other known causes of chronic liver disease, including alcoholic liver disease
History of cirrhosis and/or hepatic decompensation including ascites, hepatic encephalopathy or variceal bleeding
Alcohol consumption greater than 21 units/week for males or 14 units/week for females (one unit of alcohol is ½ pint of beer [285 mL], 1 glass of spirits [25 mL] or 1 glass of wine [125 mL])
Human immunodeficiency virus (HIV)-1 or HIV-2 infection
Weight reduction through bariatric surgery in the past 5 years or planned during the conduct of the study (including gastric banding)
Females who are pregnant or breastfeeding
Any other clinically significant disorders or prior therapy that, in the opinion of the investigator, would make the participant unsuitable for the study or unable to comply with the dosing and protocol requirements.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Eric Lefebvre, MD
Organizational Affiliation
Allergan
Official's Role
Study Director
Facility Information:
City
Dothan
State/Province
Alabama
ZIP/Postal Code
36305
Country
United States
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85054
Country
United States
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85712
Country
United States
City
Rialto
State/Province
California
ZIP/Postal Code
92377
Country
United States
City
San Diego
State/Province
California
ZIP/Postal Code
92120
Country
United States
City
San Diego
State/Province
California
ZIP/Postal Code
92161
Country
United States
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
City
Littleton
State/Province
Colorado
ZIP/Postal Code
80120
Country
United States
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
City
Tampa
State/Province
Florida
ZIP/Postal Code
33606
Country
United States
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40202
Country
United States
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70112
Country
United States
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21202
Country
United States
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
City
Chevy Chase
State/Province
Maryland
ZIP/Postal Code
20815
Country
United States
City
Lutherville
State/Province
Maryland
ZIP/Postal Code
21093
Country
United States
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
City
Worcester
State/Province
Massachusetts
ZIP/Postal Code
01655
Country
United States
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
City
Saint Paul
State/Province
Minnesota
ZIP/Postal Code
55114
Country
United States
City
Flowood
State/Province
Mississippi
ZIP/Postal Code
39232
Country
United States
City
Jackson
State/Province
Mississippi
Country
United States
City
Tupelo
State/Province
Mississippi
ZIP/Postal Code
38801
Country
United States
City
Buffalo
State/Province
New York
ZIP/Postal Code
14201
Country
United States
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
City
Raleigh
State/Province
North Carolina
ZIP/Postal Code
27612
Country
United States
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27103
Country
United States
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45249
Country
United States
City
Chattanooga
State/Province
Tennessee
ZIP/Postal Code
37421
Country
United States
City
Germantown
State/Province
Tennessee
ZIP/Postal Code
38138
Country
United States
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
City
Houston
State/Province
Texas
ZIP/Postal Code
78234
Country
United States
City
Live Oak
State/Province
Texas
ZIP/Postal Code
78233
Country
United States
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78215
Country
United States
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78233
Country
United States
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States
City
Seattle
State/Province
Washington
ZIP/Postal Code
98104
Country
United States
City
Garran
State/Province
Australian Capital Territory
ZIP/Postal Code
2605
Country
Australia
City
Herston
State/Province
Queensland
ZIP/Postal Code
4029
Country
Australia
City
Adelaide
State/Province
South Australia
ZIP/Postal Code
5000
Country
Australia
City
Bedford Park
State/Province
South Australia
ZIP/Postal Code
5042
Country
Australia
City
Clayton
State/Province
Victoria
ZIP/Postal Code
3168
Country
Australia
City
Heidelberg
State/Province
Victoria
ZIP/Postal Code
3084
Country
Australia
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3004
Country
Australia
City
Perth
State/Province
Western Australia
ZIP/Postal Code
6000
Country
Australia
City
Brussels
ZIP/Postal Code
1070
Country
Belgium
City
Brussels
ZIP/Postal Code
1200
Country
Belgium
City
Edegem
ZIP/Postal Code
2650
Country
Belgium
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
City
Angers
ZIP/Postal Code
49100
Country
France
City
Lyon cedex 04
ZIP/Postal Code
69317
Country
France
City
Montpellier Cedex 5
ZIP/Postal Code
34295
Country
France
City
Paris
ZIP/Postal Code
75012
Country
France
City
Paris
ZIP/Postal Code
75651
Country
France
City
Pessac Cedex
ZIP/Postal Code
33604
Country
France
City
Toulouse
ZIP/Postal Code
31059
Country
France
City
Vandoeuvre-les Nancy
ZIP/Postal Code
54500
Country
France
City
Villejuif
ZIP/Postal Code
94800
Country
France
City
Heidelberg
State/Province
BW
ZIP/Postal Code
69120
Country
Germany
City
Marburg
State/Province
HE
ZIP/Postal Code
35043
Country
Germany
City
Hamburg
State/Province
HH
ZIP/Postal Code
20246
Country
Germany
City
Hannover
State/Province
Niedersachsen
ZIP/Postal Code
30625
Country
Germany
City
Aachen
State/Province
NRW
ZIP/Postal Code
52074
Country
Germany
City
Koeln
State/Province
NRW
ZIP/Postal Code
50937
Country
Germany
City
Leipzig
State/Province
Sachsen
ZIP/Postal Code
04103
Country
Germany
City
Leipzig
State/Province
SN
ZIP/Postal Code
04103
Country
Germany
City
Heidelberg
State/Province
VIC
ZIP/Postal Code
3084
Country
Germany
City
Berlin
ZIP/Postal Code
13353
Country
Germany
City
Lubeck
ZIP/Postal Code
23538
Country
Germany
City
Shatin
State/Province
New Territories
Country
Hong Kong
City
Bologna
State/Province
BO
ZIP/Postal Code
40138
Country
Italy
City
Milan
State/Province
MI
ZIP/Postal Code
20122
Country
Italy
City
Rozzano
State/Province
MI
ZIP/Postal Code
20089
Country
Italy
City
Palermo
State/Province
PA
ZIP/Postal Code
90127
Country
Italy
City
Chorzow
ZIP/Postal Code
41-500
Country
Poland
City
Lodz
ZIP/Postal Code
91-347
Country
Poland
City
Myslowice
ZIP/Postal Code
41-500
Country
Poland
City
Rzeszow
ZIP/Postal Code
35-055
Country
Poland
City
Wroclaw
ZIP/Postal Code
50-349
Country
Poland
City
Alicante
ZIP/Postal Code
03010
Country
Spain
City
Barcelona
ZIP/Postal Code
08026
Country
Spain
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
City
Madrid
ZIP/Postal Code
28007
Country
Spain
City
Portsmouth
State/Province
Hampshire
ZIP/Postal Code
PO6 3LY
Country
United Kingdom
City
London
ZIP/Postal Code
E1 1BB
Country
United Kingdom
City
London
ZIP/Postal Code
NW3 2QR
Country
United Kingdom
City
Newcastle
ZIP/Postal Code
NE7 7ND
Country
United Kingdom
City
Nottingham
ZIP/Postal Code
NG7 2UH
Country
United Kingdom
12. IPD Sharing Statement
Citations:
PubMed Identifier
34951993
Citation
Qian T, Fujiwara N, Koneru B, Ono A, Kubota N, Jajoriya AK, Tung MG, Crouchet E, Song WM, Marquez CA, Panda G, Hoshida A, Raman I, Li QZ, Lewis C, Yopp A, Rich NE, Singal AG, Nakagawa S, Goossens N, Higashi T, Koh AP, Bian CB, Hoshida H, Tabrizian P, Gunasekaran G, Florman S, Schwarz ME, Hiotis SP, Nakahara T, Aikata H, Murakami E, Beppu T, Baba H, Rew Warren, Bhatia S, Kobayashi M, Kumada H, Fobar AJ, Parikh ND, Marrero JA, Rwema SH, Nair V, Patel M, Kim-Schulze S, Corey K, O'Leary JG, Klintmalm GB, Thomas DL, Dibas M, Rodriguez G, Zhang B, Friedman SL, Baumert TF, Fuchs BC, Chayama K, Zhu S, Chung RT, Hoshida Y. Molecular Signature Predictive of Long-Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development. Gastroenterology. 2022 Apr;162(4):1210-1225. doi: 10.1053/j.gastro.2021.12.250. Epub 2021 Dec 22. Erratum In: Gastroenterology. 2022 Aug;163(2):536.
Results Reference
derived
PubMed Identifier
34454994
Citation
Nielsen MJ, Leeming DJ, Goodman Z, Friedman S, Frederiksen P, Rasmussen DGK, Vig P, Seyedkazemi S, Fischer L, Torstenson R, Karsdal MA, Lefebvre E, Sanyal AJ, Ratziu V. Comparison of ADAPT, FIB-4 and APRI as non-invasive predictors of liver fibrosis and NASH within the CENTAUR screening population. J Hepatol. 2021 Dec;75(6):1292-1300. doi: 10.1016/j.jhep.2021.08.016. Epub 2021 Aug 27.
Results Reference
derived
PubMed Identifier
33666272
Citation
Parthasarathy G, Malhi H. Macrophage Heterogeneity in NASH: More Than Just Nomenclature. Hepatology. 2021 Jul;74(1):515-518. doi: 10.1002/hep.31790. Epub 2021 May 22. No abstract available.
Results Reference
derived
PubMed Identifier
31943293
Citation
Ratziu V, Sanyal A, Harrison SA, Wong VW, Francque S, Goodman Z, Aithal GP, Kowdley KV, Seyedkazemi S, Fischer L, Loomba R, Abdelmalek MF, Tacke F. Cenicriviroc Treatment for Adults With Nonalcoholic Steatohepatitis and Fibrosis: Final Analysis of the Phase 2b CENTAUR Study. Hepatology. 2020 Sep;72(3):892-905. doi: 10.1002/hep.31108. Epub 2020 Jul 21.
Results Reference
derived
PubMed Identifier
27347680
Citation
Lefebvre E, Moyle G, Reshef R, Richman LP, Thompson M, Hong F, Chou HL, Hashiguchi T, Plato C, Poulin D, Richards T, Yoneyama H, Jenkins H, Wolfgang G, Friedman SL. Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis. PLoS One. 2016 Jun 27;11(6):e0158156. doi: 10.1371/journal.pone.0158156. eCollection 2016.
Results Reference
derived
PubMed Identifier
26944023
Citation
Friedman S, Sanyal A, Goodman Z, Lefebvre E, Gottwald M, Fischer L, Ratziu V. Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design. Contemp Clin Trials. 2016 Mar;47:356-65. doi: 10.1016/j.cct.2016.02.012. Epub 2016 Mar 2.
Results Reference
derived
Learn more about this trial
Efficacy and Safety Study of Cenicriviroc for the Treatment of Nonalcoholic Steatohepatitis (NASH) in Adult Participants With Liver Fibrosis
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