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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02217475
Recruitment Status : Completed
First Posted : August 15, 2014
Results First Posted : May 10, 2019
Last Update Posted : May 10, 2019
Sponsor:
Information provided by (Responsible Party):
Tobira Therapeutics, Inc.

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.

Condition or disease Intervention/treatment Phase
Nonalcoholic Steatohepatitis Drug: Cenicriviroc Drug: Placebo Phase 2

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 289 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: CENTAUR: Efficacy and Safety Study of Cenicriviroc for the Treatment of Nonalcoholic Steatohepatitis (NASH) in Adult Subjects With Liver Fibrosis
Actual Study Start Date : September 18, 2014
Actual Primary Completion Date : June 30, 2016
Actual Study Completion Date : June 22, 2017


Arm Intervention/treatment
Experimental: Cenicriviroc (CVC) 150mg/CVC 150 mg
CVC 150 mg tablet in Years 1 and 2.
Drug: Cenicriviroc
CVC 150 mg, administered orally once daily and taken every morning with food.
Other Name: TBR-652

Experimental: Placebo/CVC 150 mg
Placebo-matching CVC tablet in Year 1 then CVC 150 mg tablet in Year 2.
Drug: Cenicriviroc
CVC 150 mg, administered orally once daily and taken every morning with food.
Other Name: TBR-652

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

Placebo Comparator: Placebo/Placebo
Placebo-matching cenicriviroc (CVC) tablet in Years 1 and 2.
Drug: Placebo
Placebo administered orally once daily and taken every morning with food.




Primary Outcome Measures :
  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 [ Time Frame: 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 :
  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 [ Time Frame: 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.

  2. 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 [ Time Frame: 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.

  3. Number of Participants With Complete Resolution of Steatohepatitis With no Concurrent Worsening of Fibrosis Stage at Year 1 [ Time Frame: 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.

  4. Number of Participants With Complete Resolution of Steatohepatitis With no Concurrent Worsening of Fibrosis Stage at Year 2 [ Time Frame: 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.

  5. Number of Participants With Improvement in Fibrosis by at Least 1 Stage (NASH CRN System) and no Worsening of Steatohepatitis at Year 1 [ Time Frame: 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.

  6. Number of Participants With Improvement in Fibrosis by at Least 1 Stage (NASH CRN System) and no Worsening of Steatohepatitis at Year 2 [ Time Frame: 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.

  7. Number of Participants With Deaths, Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), TEAEs Leading Study Drug to Discontinuation [ Time Frame: Years 1 and 2 ]
    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.

  8. Number of Participants With Clinically Significant Changes in Vital Signs [ Time Frame: Years 1 and 2 ]
    Vital signs included blood pressure, temperature, heart rate, and respiration rate. Vital signs were reviewed by the Investigator for clinically significant changes.

  9. Number of Participants With Clinical Laboratory Abnormalities [ Time Frame: Years 1 and 2 ]
    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.

  10. Number of Participants With Clinically Abnormal in Electrocardiogram (ECG) Findings [ Time Frame: Years 1 and 2 ]
    A 12-lead ECG was performed. ECG results were reviewed by the Investigator for clinically notable abnormalities.

  11. Number of Participants With Hepatic Histological Improvement in NAS at Year 2 [ Time Frame: 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.

  12. Change From Baseline in the 3 Categorical Features of NAS (Steatosis, Lobular Inflammation, Hepatocellular Ballooning) at Year 1 [ Time Frame: 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.

  13. Change From Baseline in the 3 Categorical Features of NAS (Steatosis, Lobular Inflammation, Hepatocellular Ballooning) at Year 2 [ Time Frame: 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.

  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 [ Time Frame: 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.

  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 [ Time Frame: 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.

  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 [ Time Frame: 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).

  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 [ Time Frame: 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).

  18. Change From Baseline in Morphometric Quantitative Collagen on Liver Biopsy at Year 1 [ Time Frame: 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.

  19. Change From Baseline in Morphometric Quantitative Collagen on Liver Biopsy at Year 2 [ Time Frame: 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.

  20. Change From Baseline in Hepatic Tissue Fibrogenic Protein Alpha-Smooth Muscle Actin (α-SMA) at Year 1 [ Time Frame: Baseline (Day 1) to 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.

  21. Change From Baseline in Hepatic Tissue Fibrogenic Protein Alpha-Smooth Muscle Actin (α-SMA) at Year 2 [ Time Frame: Baseline (Day 1) to 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.

  22. Change From Baseline in Morphometric Quantitative Fat Content on Liver Biopsy at Year 1 [ Time Frame: 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.

  23. Change From Baseline in Morphometric Quantitative Fat Content on Liver Biopsy at Year 2 [ Time Frame: 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.

  24. Change From Baseline in Histologic Fibrosis Stage (NASH CRN System and Ishak Scale Score) at Year 1 [ Time Frame: Baseline (Day 1) to 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.

  25. Change From Baseline in Histologic Fibrosis Stage (NASH CRN System and Ishak Scale Score) at Year 2 [ Time Frame: Baseline (Day 1) to 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.

  26. Change From Baseline in Portal Inflammation Grade on Liver Biopsy at Year 1 [ Time Frame: Baseline (Day 1) to 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.

  27. Change From Baseline in Portal Inflammation Grade on Liver Biopsy at Year 2 [ Time Frame: Baseline (Day 1) to 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.

  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 [ Time Frame: Baseline (Month 0) to 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.

  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 [ Time Frame: Baseline (Month 0) to 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.

  30. Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Fibrosis-4 (FIB-4) at Months 3, 6 and 12 [ Time Frame: Baseline (Month 0) to 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.

  31. Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Fibrosis-4 (FIB-4) at Months 15, 18 and 24 [ Time Frame: Baseline (Month 0) to 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.

  32. Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Hyaluronic Acid at Months 6 and 12 [ Time Frame: Baseline (Month 0) to Months 6 and 12 ]
    Hyaluronic acid is a non-invasive hepatic fibrosis marker. A negative change from Baseline indicates decreased fibrosis.

  33. Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Hyaluronic Acid at Months 18 and 24 [ Time Frame: Baseline (Month 0) to Months 18 and 24 ]
    Hyaluronic acid is a non-invasive hepatic fibrosis marker. A positive change from Baseline indicates increased fibrosis.

  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 [ Time Frame: Baseline (Month 0) to 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.

  35. Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: NAFLD Fibrosis Score (NFS) at Months 15, 18 and 24 [ Time Frame: Baseline (Month 0) to 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.

  36. Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score at Months 6 and 12 [ Time Frame: Baseline (Month 0) to 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.

  37. Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score at Months 18 and 24 [ Time Frame: Baseline (Month 0) to 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.

  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 [ Time Frame: Baseline (Month 0) to 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.

  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 [ Time Frame: Baseline (Month 0) to 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.

  40. Change From Baseline in Weight at Months 3, 6 and 12 [ Time Frame: Baseline (Day 1) to Months 3, 6 and 12 ]
    A negative change from Baseline represents decreased weight.

  41. Change From Baseline in Weight at Months 15, 18 and 24 [ Time Frame: Baseline (Day 1) to Months 15, 18 and 24 ]
    A negative change from Baseline represents decreased weight.

  42. Change From Baseline in Body Mass Index (BMI) at Months 3, 6 and 12 [ Time Frame: Baseline (Day 1) to 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.

  43. Change From Baseline in Body Mass Index (BMI) at Months 15, 18 and 24 [ Time Frame: Baseline (Day 1) to 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.

  44. Change From Baseline in Waist Circumference at Months 3, 6 and 12 [ Time Frame: Baseline (Day 1) to Months 3, 6 and 12 ]
    A negative change from Baseline represents decreased in waist circumference.

  45. Change From Baseline in Waist Circumference at Months 15, 18 and 24 [ Time Frame: Baseline (Day 1) to Months 15, 18 and 24 ]
    A negative change from Baseline represents decreased in waist circumference.

  46. Change From Baseline in Hip Circumference at Months 3, 6 and 12 [ Time Frame: Baseline (Day 1) to Months 3, 6 and 12 ]
    A negative change from Baseline represents decreased hip circumference.

  47. Change From Baseline in Hip Circumference at Months 15, 18 and 24 [ Time Frame: Baseline (Day 1) to Months 15, 18 and 24 ]
    A negative change from Baseline represents decreased hip circumference.

  48. Change From Baseline in Forearm Circumference at Months 3, 6 and 12 [ Time Frame: Baseline (Day 1) to Months 3, 6 and 12 ]
    A negative change from Baseline represents decreased forearm circumference.

  49. Change From Baseline in Forearm Circumference at Months 15, 18 and 24 [ Time Frame: Baseline (Day 1) to Months 15, 18 and 24 ]
    A negative change from Baseline represents decreased forearm circumference.

  50. Change From Baseline in Tricep Skinfold Thickness at Months 3, 6 and 12 [ Time Frame: Baseline (Day 1) to Months 3, 6 and 12 ]
    A negative change from Baseline represents decreased Tricep Skinfold Thickness.

  51. Change From Baseline in Tricep Skinfold Thickness at Months 15, 18 and 24 [ Time Frame: Baseline (Day 1) to Months 15, 18 and 24 ]
    A negative change from Baseline represents decreased Tricep Skinfold Thickness.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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):

    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)

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02217475


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Locations
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United States, Alabama
Dothan, Alabama, United States, 36305
United States, Arizona
Phoenix, Arizona, United States, 85054
Tucson, Arizona, United States, 85712
United States, California
Rialto, California, United States, 92377
San Diego, California, United States, 92120
San Diego, California, United States, 92161
San Francisco, California, United States, 94115
United States, Colorado
Littleton, Colorado, United States, 80120
United States, Florida
Miami, Florida, United States, 33136
Tampa, Florida, United States, 33606
United States, Illinois
Chicago, Illinois, United States, 60612
United States, Kentucky
Louisville, Kentucky, United States, 40202
United States, Louisiana
New Orleans, Louisiana, United States, 70112
United States, Maryland
Baltimore, Maryland, United States, 21202
Baltimore, Maryland, United States, 21287
Chevy Chase, Maryland, United States, 20815
Lutherville, Maryland, United States, 21093
United States, Massachusetts
Boston, Massachusetts, United States, 02114
Worcester, Massachusetts, United States, 01655
United States, Michigan
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
Saint Paul, Minnesota, United States, 55114
United States, Mississippi
Flowood, Mississippi, United States, 39232
Jackson, Mississippi, United States
Tupelo, Mississippi, United States, 38801
United States, New York
Buffalo, New York, United States, 14201
New York, New York, United States, 10029
United States, North Carolina
Durham, North Carolina, United States, 27710
Raleigh, North Carolina, United States, 27612
Winston-Salem, North Carolina, United States, 27103
United States, Ohio
Cincinnati, Ohio, United States, 45249
United States, Tennessee
Chattanooga, Tennessee, United States, 37421
Germantown, Tennessee, United States, 38138
United States, Texas
Houston, Texas, United States, 77030
Houston, Texas, United States, 78234
Live Oak, Texas, United States, 78233
San Antonio, Texas, United States, 78215
San Antonio, Texas, United States, 78233
United States, Utah
Salt Lake City, Utah, United States, 84132
United States, Virginia
Richmond, Virginia, United States, 23298
United States, Washington
Seattle, Washington, United States, 98104
Australia, Australian Capital Territory
Garran, Australian Capital Territory, Australia, 2605
Australia, Queensland
Herston, Queensland, Australia, 4029
Australia, South Australia
Adelaide, South Australia, Australia, 5000
Bedford Park, South Australia, Australia, 5042
Australia, Victoria
Clayton, Victoria, Australia, 3168
Heidelberg, Victoria, Australia, 3084
Melbourne, Victoria, Australia, 3004
Australia, Western Australia
Perth, Western Australia, Australia, 6000
Belgium
Brussels, Belgium, 1070
Brussels, Belgium, 1200
Edegem, Belgium, 2650
Leuven, Belgium, 3000
France
Angers, France, 49100
Lyon cedex 04, France, 69317
Montpellier Cedex 5, France, 34295
Paris, France, 75012
Paris, France, 75651
Pessac Cedex, France, 33604
Toulouse, France, 31059
Vandoeuvre-les Nancy, France, 54500
Villejuif, France, 94800
Germany
Heidelberg, BW, Germany, 69120
Marburg, HE, Germany, 35043
Hamburg, HH, Germany, 20246
Hannover, Niedersachsen, Germany, 30625
Aachen, NRW, Germany, 52074
Koeln, NRW, Germany, 50937
Leipzig, Sachsen, Germany, 04103
Leipzig, SN, Germany, 04103
Heidelberg, VIC, Germany, 3084
Berlin, Germany, 13353
Lubeck, Germany, 23538
Hong Kong
Shatin, New Territories, Hong Kong
Italy
Bologna, BO, Italy, 40138
Milan, MI, Italy, 20122
Rozzano, MI, Italy, 20089
Palermo, PA, Italy, 90127
Poland
Chorzow, Poland, 41-500
Lodz, Poland, 91-347
Myslowice, Poland, 41-500
Rzeszow, Poland, 35-055
Wroclaw, Poland, 50-349
Spain
Alicante, Spain, 03010
Barcelona, Spain, 08026
Barcelona, Spain, 08035
Barcelona, Spain, 08036
Madrid, Spain, 28007
United Kingdom
Portsmouth, Hampshire, United Kingdom, PO6 3LY
London, United Kingdom, E1 1BB
London, United Kingdom, NW3 2QR
Newcastle, United Kingdom, NE7 7ND
Nottingham, United Kingdom, NG7 2UH
Sponsors and Collaborators
Tobira Therapeutics, Inc.
Investigators
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Study Director: Eric Lefebvre, MD Allergan

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Tobira Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT02217475     History of Changes
Other Study ID Numbers: 652-2-203
2016-004754-15 ( EudraCT Number )
First Posted: August 15, 2014    Key Record Dates
Results First Posted: May 10, 2019
Last Update Posted: May 10, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Fatty Liver
Liver Cirrhosis
Non-alcoholic Fatty Liver Disease
Liver Diseases
Digestive System Diseases
TAK-652
CCR5 Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents