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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02217475

Registration number

NCT02217475

Ethics application status

Date submitted

13/08/2014

Date registered

15/08/2014

Date last updated

10/05/2019

Titles & IDs

Public title

Efficacy and Safety Study of Cenicriviroc for the Treatment of Nonalcoholic Steatohepatitis (NASH) in Adult Participants With Liver Fibrosis

Scientific title

CENTAUR: Efficacy and Safety Study of Cenicriviroc for the Treatment of Nonalcoholic Steatohepatitis (NASH) in Adult Subjects With Liver Fibrosis

Secondary ID [1]

2016-004754-15

Secondary ID [2]

652-2-203

Universal Trial Number (UTN)

Trial acronym

CENTAUR

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Nonalcoholic Steatohepatitis

Condition category

Condition code

Oral and Gastrointestinal

Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Metabolic and Endocrine

Metabolic disorders

Diet and Nutrition

Obesity

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Treatment: Drugs - Cenicriviroc
Treatment: Drugs - Placebo

Experimental: Cenicriviroc (CVC) 150mg/CVC 150 mg - CVC 150 mg tablet in Years 1 and 2.

Experimental: Placebo/CVC 150 mg - Placebo-matching CVC tablet in Year 1 then CVC 150 mg tablet in Year 2.

Placebo comparator: Placebo/Placebo - Placebo-matching cenicriviroc (CVC) tablet in Years 1 and 2.

Treatment: Drugs: Cenicriviroc
CVC 150 mg, administered orally once daily and taken every morning with food.

Treatment: Drugs: Placebo
Placebo administered orally once daily and taken every morning with food.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Control group

Outcomes

Primary outcome [1]

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

Assessment method [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.

Timepoint [1]

Year 1

Secondary outcome [1]

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

Assessment method [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.

Timepoint [1]

Year 1

Secondary outcome [2]

Assessment method [2]

Timepoint [2]

Year 2

Secondary outcome [3]

Number of Participants With Complete Resolution of Steatohepatitis With no Concurrent Worsening of Fibrosis Stage at Year 1

Assessment method [3]

Timepoint [3]

Year 1

Secondary outcome [4]

Number of Participants With Complete Resolution of Steatohepatitis With no Concurrent Worsening of Fibrosis Stage at Year 2

Assessment method [4]

Timepoint [4]

Year 2

Secondary outcome [5]

Number of Participants With Improvement in Fibrosis by at Least 1 Stage (NASH CRN System) and no Worsening of Steatohepatitis at Year 1

Assessment method [5]

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.

Timepoint [5]

Year 1

Secondary outcome [6]

Number of Participants With Improvement in Fibrosis by at Least 1 Stage (NASH CRN System) and no Worsening of Steatohepatitis at Year 2

Assessment method [6]

Timepoint [6]

Year 2

Secondary outcome [7]

Number of Participants With Deaths, Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), TEAEs Leading Study Drug to Discontinuation

Assessment method [7]

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.

Timepoint [7]

Years 1 and 2

Secondary outcome [8]

Number of Participants With Clinically Significant Changes in Vital Signs

Assessment method [8]

Vital signs included blood pressure, temperature, heart rate, and respiration rate. Vital signs were reviewed by the Investigator for clinically significant changes.

Timepoint [8]

Years 1 and 2

Secondary outcome [9]

Number of Participants With Clinical Laboratory Abnormalities

Assessment method [9]

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.

Timepoint [9]

Years 1 and 2

Secondary outcome [10]

Number of Participants With Clinically Abnormal in Electrocardiogram (ECG) Findings

Assessment method [10]

A 12-lead ECG was performed. ECG results were reviewed by the Investigator for clinically notable abnormalities.

Timepoint [10]

Years 1 and 2

Secondary outcome [11]

Number of Participants With Hepatic Histological Improvement in NAS at Year 2

Assessment method [11]

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.

Timepoint [11]

Year 2

Secondary outcome [12]

Change From Baseline in the 3 Categorical Features of NAS (Steatosis, Lobular Inflammation, Hepatocellular Ballooning) at Year 1

Assessment method [12]

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.

Timepoint [12]

Year 1

Secondary outcome [13]

Change From Baseline in the 3 Categorical Features of NAS (Steatosis, Lobular Inflammation, Hepatocellular Ballooning) at Year 2

Assessment method [13]

Timepoint [13]

Year 2

Secondary outcome [14]

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

Assessment method [14]

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.

Timepoint [14]

Year 1

Secondary outcome [15]

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

Assessment method [15]

Timepoint [15]

Year 2

Secondary outcome [16]

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

Assessment method [16]

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).

Timepoint [16]

Year 1

Secondary outcome [17]

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

Assessment method [17]

Timepoint [17]

Year 2

Secondary outcome [18]

Change From Baseline in Morphometric Quantitative Collagen on Liver Biopsy at Year 1

Assessment method [18]

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.

Timepoint [18]

Year 1

Secondary outcome [19]

Change From Baseline in Morphometric Quantitative Collagen on Liver Biopsy at Year 2

Assessment method [19]

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.

Timepoint [19]

Year 2

Secondary outcome [20]

Change From Baseline in Hepatic Tissue Fibrogenic Protein Alpha-Smooth Muscle Actin (a-SMA) at Year 1

Assessment method [20]

The hepatic tissue fibrogenic protein a-SMA level was determined as percent a-SMA + area using a-SMA stain on liver biopsy at Year 1. A positive change from Baseline indicates worsening.

Timepoint [20]

Baseline (Day 1) to Year 1

Secondary outcome [21]

Change From Baseline in Hepatic Tissue Fibrogenic Protein Alpha-Smooth Muscle Actin (a-SMA) at Year 2

Assessment method [21]

The hepatic tissue fibrogenic protein a-SMA level was determined as percent a-SMA + area using a-SMA stain on liver biopsy at Year 2. A positive change from Baseline indicates worsening.

Timepoint [21]

Baseline (Day 1) to Year 2

Secondary outcome [22]

Change From Baseline in Morphometric Quantitative Fat Content on Liver Biopsy at Year 1

Assessment method [22]

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.

Timepoint [22]

Year 1

Secondary outcome [23]

Change From Baseline in Morphometric Quantitative Fat Content on Liver Biopsy at Year 2

Assessment method [23]

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.

Timepoint [23]

Year 2

Secondary outcome [24]

Change From Baseline in Histologic Fibrosis Stage (NASH CRN System and Ishak Scale Score) at Year 1

Assessment method [24]

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.

Timepoint [24]

Baseline (Day 1) to Year 1

Secondary outcome [25]

Change From Baseline in Histologic Fibrosis Stage (NASH CRN System and Ishak Scale Score) at Year 2

Assessment method [25]

Timepoint [25]

Baseline (Day 1) to Year 2

Secondary outcome [26]

Change From Baseline in Portal Inflammation Grade on Liver Biopsy at Year 1

Assessment method [26]

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.

Timepoint [26]

Baseline (Day 1) to Year 1

Secondary outcome [27]

Change From Baseline in Portal Inflammation Grade on Liver Biopsy at Year 2

Assessment method [27]

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.

Timepoint [27]

Baseline (Day 1) to Year 2

Secondary outcome [28]

Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Aspartate Aminotransferase to Platelet Count Ratio Index (APRI) at Months 3, 6 and 12

Assessment method [28]

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.

Timepoint [28]

Baseline (Month 0) to Months 3, 6 and 12

Secondary outcome [29]

Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Aspartate Aminotransferase to Platelet Count Ratio Index (APRI) at Months 15, 18 and 24

Assessment method [29]

Timepoint [29]

Baseline (Month 0) to Months 15, 18 and 24

Secondary outcome [30]

Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Fibrosis-4 (FIB-4) at Months 3, 6 and 12

Assessment method [30]

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.

Timepoint [30]

Baseline (Month 0) to Months 3, 6 and 12

Secondary outcome [31]

Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Fibrosis-4 (FIB-4) at Months 15, 18 and 24

Assessment method [31]

Timepoint [31]

Baseline (Month 0) to Months 15, 18 and 24

Secondary outcome [32]

Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Hyaluronic Acid at Months 6 and 12

Assessment method [32]

Hyaluronic acid is a non-invasive hepatic fibrosis marker. A negative change from Baseline indicates decreased fibrosis.

Timepoint [32]

Baseline (Month 0) to Months 6 and 12

Secondary outcome [33]

Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Hyaluronic Acid at Months 18 and 24

Assessment method [33]

Hyaluronic acid is a non-invasive hepatic fibrosis marker. A positive change from Baseline indicates increased fibrosis.

Timepoint [33]

Baseline (Month 0) to Months 18 and 24

Secondary outcome [34]

Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Nonalcoholic Fatty Liver Disease (NAFLD) Fibrosis Score (NFS) at Months 3, 6 and 12

Assessment method [34]

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.

Timepoint [34]

Baseline (Month 0) to Months 3, 6 and 12

Secondary outcome [35]

Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: NAFLD Fibrosis Score (NFS) at Months 15, 18 and 24

Assessment method [35]

Timepoint [35]

Baseline (Month 0) to Months 15, 18 and 24

Secondary outcome [36]

Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score at Months 6 and 12

Assessment method [36]

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.

Timepoint [36]

Baseline (Month 0) to Months 6 and 12

Secondary outcome [37]

Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score at Months 18 and 24

Assessment method [37]

Timepoint [37]

Baseline (Month 0) to Months 18 and 24

Secondary outcome [38]

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

Assessment method [38]

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.

Timepoint [38]

Baseline (Month 0) to Months 3, 6 and 12

Secondary outcome [39]

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

Assessment method [39]

Timepoint [39]

Baseline (Month 0) to Months 15, 18 and 24

Secondary outcome [40]

Change From Baseline in Weight at Months 3, 6 and 12

Assessment method [40]

A negative change from Baseline represents decreased weight.

Timepoint [40]

Baseline (Day 1) to Months 3, 6 and 12

Secondary outcome [41]

Change From Baseline in Weight at Months 15, 18 and 24

Assessment method [41]

A negative change from Baseline represents decreased weight.

Timepoint [41]

Baseline (Day 1) to Months 15, 18 and 24

Secondary outcome [42]

Change From Baseline in Body Mass Index (BMI) at Months 3, 6 and 12

Assessment method [42]

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.

Timepoint [42]

Baseline (Day 1) to Months 3, 6 and 12

Secondary outcome [43]

Change From Baseline in Body Mass Index (BMI) at Months 15, 18 and 24

Assessment method [43]

Timepoint [43]

Baseline (Day 1) to Months 15, 18 and 24

Secondary outcome [44]

Change From Baseline in Waist Circumference at Months 3, 6 and 12

Assessment method [44]

A negative change from Baseline represents decreased in waist circumference.

Timepoint [44]

Baseline (Day 1) to Months 3, 6 and 12

Secondary outcome [45]

Change From Baseline in Waist Circumference at Months 15, 18 and 24

Assessment method [45]

A negative change from Baseline represents decreased in waist circumference.

Timepoint [45]

Baseline (Day 1) to Months 15, 18 and 24

Secondary outcome [46]

Change From Baseline in Hip Circumference at Months 3, 6 and 12

Assessment method [46]

A negative change from Baseline represents decreased hip circumference.

Timepoint [46]

Baseline (Day 1) to Months 3, 6 and 12

Secondary outcome [47]

Change From Baseline in Hip Circumference at Months 15, 18 and 24

Assessment method [47]

A negative change from Baseline represents decreased hip circumference.

Timepoint [47]

Baseline (Day 1) to Months 15, 18 and 24

Secondary outcome [48]

Change From Baseline in Forearm Circumference at Months 3, 6 and 12

Assessment method [48]

A negative change from Baseline represents decreased forearm circumference.

Timepoint [48]

Baseline (Day 1) to Months 3, 6 and 12

Secondary outcome [49]

Change From Baseline in Forearm Circumference at Months 15, 18 and 24

Assessment method [49]

A negative change from Baseline represents decreased forearm circumference.

Timepoint [49]

Baseline (Day 1) to Months 15, 18 and 24

Secondary outcome [50]

Change From Baseline in Tricep Skinfold Thickness at Months 3, 6 and 12

Assessment method [50]

A negative change from Baseline represents decreased Tricep Skinfold Thickness.

Timepoint [50]

Baseline (Day 1) to Months 3, 6 and 12

Secondary outcome [51]

Change From Baseline in Tricep Skinfold Thickness at Months 15, 18 and 24

Assessment method [51]

A negative change from Baseline represents decreased Tricep Skinfold Thickness.

Timepoint [51]

Baseline (Day 1) to Months 15, 18 and 24

Eligibility

Key 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):

1. Documented evidence of type 2 diabetes mellitus
2. 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)
3. 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)

Minimum age

18 Years

Maximum age

75 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

* Hepatitis B surface Antigen (HBsAg) positive
* Hepatitis C antibody (HCVAb) positive with the following 2 exceptions:

1. 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
2. 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.

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data

Intervention assignment

Crossover

Other design features

Phase

Phase 2

Type of endpoint/s

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Data analysis

Reason for early stopping/withdrawal

Other reasons

Date of first participant enrolment

Anticipated

Actual

18/09/2014

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

22/06/2017

Sample size

Target

Accrual to date

Final

289

Recruitment in Australia

Recruitment state(s)

ACT,QLD,SA,VIC,WA

Recruitment hospital [1]

- Garran

Recruitment hospital [2]

- Herston

Recruitment hospital [3]

- Adelaide

Recruitment hospital [4]

- Bedford Park

Recruitment hospital [5]

- Clayton

Recruitment hospital [6]

- Heidelberg

Recruitment hospital [7]

- Melbourne

Recruitment hospital [8]

- Perth

Recruitment postcode(s) [1]

2605 - Garran

Recruitment postcode(s) [2]

4029 - Herston

Recruitment postcode(s) [3]

5000 - Adelaide

Recruitment postcode(s) [4]

5042 - Bedford Park

Recruitment postcode(s) [5]

3168 - Clayton

Recruitment postcode(s) [6]

3084 - Heidelberg

Recruitment postcode(s) [7]

3004 - Melbourne

Recruitment postcode(s) [8]

6000 - Perth

Recruitment outside Australia

Country [1]

United States of America

State/province [1]

Alabama

Country [2]

United States of America

State/province [2]

Arizona

Country [3]

United States of America

State/province [3]

California

Country [4]

United States of America

State/province [4]

Colorado

Country [5]

United States of America

State/province [5]

Florida

Country [6]

United States of America

State/province [6]

Illinois

Country [7]

United States of America

State/province [7]

Kentucky

Country [8]

United States of America

State/province [8]

Louisiana

Country [9]

United States of America

State/province [9]

Maryland

Country [10]

United States of America

State/province [10]

Massachusetts

Country [11]

United States of America

State/province [11]

Michigan

Country [12]

United States of America

State/province [12]

Minnesota

Country [13]

United States of America

State/province [13]

Mississippi

Country [14]

United States of America

State/province [14]

New York

Country [15]

United States of America

State/province [15]

North Carolina

Country [16]

United States of America

State/province [16]

Ohio

Country [17]

United States of America

State/province [17]

Tennessee

Country [18]

United States of America

State/province [18]

Texas

Country [19]

United States of America

State/province [19]

Utah

Country [20]

United States of America

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Virginia

Country [21]

United States of America

State/province [21]

Washington

Country [22]

Belgium

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Brussels

Country [23]

Belgium

State/province [23]

Edegem

Country [24]

Belgium

State/province [24]

Leuven

Country [25]

France

State/province [25]

Angers

Country [26]

France

State/province [26]

Lyon cedex 04

Country [27]

France

State/province [27]

Montpellier Cedex 5

Country [28]

France

State/province [28]

Paris

Country [29]

France

State/province [29]

Pessac Cedex

Country [30]

France

State/province [30]

Toulouse

Country [31]

France

State/province [31]

Vandoeuvre-les Nancy

Country [32]

France

State/province [32]

Villejuif

Country [33]

Germany

State/province [33]

Country [34]

Germany

State/province [34]

Country [35]

Germany

State/province [35]

Country [36]

Germany

State/province [36]

Niedersachsen

Country [37]

Germany

State/province [37]

NRW

Country [38]

Germany

State/province [38]

Sachsen

Country [39]

Germany

State/province [39]

Country [40]

Germany

State/province [40]

VIC

Country [41]

Germany

State/province [41]

Berlin

Country [42]

Germany

State/province [42]

Lubeck

Country [43]

Hong Kong

State/province [43]

New Territories

Country [44]

Italy

State/province [44]

Country [45]

Italy

State/province [45]

Country [46]

Italy

State/province [46]

Country [47]

Poland

State/province [47]

Chorzow

Country [48]

Poland

State/province [48]

Lodz

Country [49]

Poland

State/province [49]

Myslowice

Country [50]

Poland

State/province [50]

Rzeszow

Country [51]

Poland

State/province [51]

Wroclaw

Country [52]

Spain

State/province [52]

Alicante

Country [53]

Spain

State/province [53]

Barcelona

Country [54]

Spain

State/province [54]

Madrid

Country [55]

United Kingdom

State/province [55]

Hampshire

Country [56]

United Kingdom

State/province [56]

London

Country [57]

United Kingdom

State/province [57]

Newcastle

Country [58]

United Kingdom

State/province [58]

Nottingham

Funding & Sponsors

Primary sponsor type

Commercial sector/industry

Name

Tobira Therapeutics, Inc.

Country

Ethics approval

Ethics application status

Summary

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.

Trial website

https://clinicaltrials.gov/study/NCT02217475

Trial related presentations / publications

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. doi: 10.1053/j.gastro.2022.06.017.
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.
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.
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.
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.
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.

Public notes

Contacts

Principal investigator

Name

Eric Lefebvre, MD

Address

Allergan

Country

Phone

Contact person for public queries

Name

Address

Country

Phone

Contact person for scientific queries

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results are available at https://clinicaltrials.gov/study/NCT02217475

Trial Review

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02217475