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AURORA: A Study for the Efficacy and Safety of Cenicriviroc (CVC) for the Treatment of Liver Fibrosis in Adults With Nonalcoholic Steatohepatitis (NASH) (AURORA)

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ClinicalTrials.gov Identifier: NCT03028740
Recruitment Status : Terminated (This study was terminated early due to lack of efficacy based on the results of the planned interim analysis of Part 1 data.)
First Posted : January 23, 2017
Results First Posted : March 10, 2022
Last Update Posted : March 10, 2022
Sponsor:
Information provided by (Responsible Party):
Tobira Therapeutics, Inc.

Tracking Information
First Submitted Date  ICMJE January 13, 2017
First Posted Date  ICMJE January 23, 2017
Results First Submitted Date  ICMJE January 4, 2022
Results First Posted Date  ICMJE March 10, 2022
Last Update Posted Date March 10, 2022
Actual Study Start Date  ICMJE April 5, 2017
Actual Primary Completion Date January 12, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 4, 2022)
  • Part 1: Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage and No Worsening of Steatohepatitis on Liver Histology at Month 12 [ Time Frame: Month 12 ]
    Fibrosis stage was evaluated using the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Fibrosis Staging System with stages: 0=none; 1=perisinusoidal or periportal; 1A=mild, zone 3, perisinusoidal; 1B=moderate, zone 3, perisinusoidal; 1C=portal/periportal; 2=perisinusoidal and portal/periportal; 3=bridging fibrosis; 4=cirrhosis. No worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade as per scoring in relevant nonalcoholic fatty liver disease activity score (NAS) categories. NAS is a semiquantitative scoring system based on the unweighted sum of: steatosis (0=<5% to 3=>66%), lobular inflammation (0=no foci to 3=>4 foci/200x), and hepatocellular ballooning (0=none to 2=many cells/prominent ballooning) scores. Improvement in fibrosis is a decrease in the NASH CRN fibrosis stage.
  • Time to First Occurrence of Adjudicated Events in the Full Study Cohort [ Time Frame: From first dose of study drug to onset of first occurrence of the event (Up to approximately 42 months) ]
    Time to first occurrence from Baseline was defined as the number of days from the first dose of randomized investigational product to the onset of the first occurrence of any of the following adjudicated events: death (all cause), histopathologic progression to cirrhosis, liver transplant, model for end stage liver disease (MELD) score ≥15, ascites, hospitalization for onset of: variceal bleed, hepatic encephalopathy, spontaneous bacterial peritonitis. MELD is a scoring system for assessing the severity of chronic liver disease and uses the participant's values for total bilirubin, serum creatinine, and the international normalized ratio for prothrombin time to predict survival. MELD score ranges from 6 (less ill) to 40 (gravely ill) with scores and mortality probability being: Score 40=71.3% mortality; Scores 30-39=52.6% mortality; Scores 20-29=19.6% mortality; Scores10-19=6.0% mortality; Score 9 or less=1.9% mortality.
Original Primary Outcome Measures  ICMJE
 (submitted: January 18, 2017)
  • Superiority of CVC compared to placebo on liver histology at Month 12 relative to the Screening biopsy [ Time Frame: Measurements at Baseline and 12 months ]
    Proportion of subjects with improvement in fibrosis by at least 1 stage (NASH CRN system) AND no worsening of steatohepatitis
  • Superiority of CVC compared to placebo on the composite endpoint of histopathologic progression to cirrhosis, liver-related clinical outcomes, and all-cause mortality [ Time Frame: Time to accrue a pre-specified number of adjudicated events, End of Study, estimated to be 5 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 4, 2022)
  • Part 1: Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages and No Worsening of Steatohepatitis on Liver Histology at Month 12 [ Time Frame: Month 12 ]
    Fibrosis stage was evaluated using the NASH CRN Fibrosis Staging System with stages: 0=none; 1=perisinusoidal or periportal; 1A=mild, zone 3, perisinusoidal; 1B=moderate, zone 3, perisinusoidal; 1C=portal/periportal; 2=perisinusoidal and portal/periportal; 3=bridging fibrosis; 4=cirrhosis. No worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade as per scoring in relevant NAS categories. NAS is a semiquantitative scoring system based on the unweighted sum of: steatosis (0=<5% to 3=>66%), lobular inflammation (0=no foci to 3=>4 foci/200x), and hepatocellular ballooning (0=none to 2=many cells/prominent ballooning) scores. Improvement in fibrosis is a decrease in the NASH CRN fibrosis stage.
  • Part 1: Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage Regardless of Effect on Steatohepatitis at Month 12 [ Time Frame: Month 12 ]
    Fibrosis stage was evaluated using the NASH CRN Fibrosis Staging System with stages 0=none, 1=perisinusoidal or periportal, 1A=mild, zone 3, perisinusoidal, 1B=moderate, zone 3, perisinusoidal, 1C=portal/periportal, 2=perisinusoidal and portal/periportal, 3=bridging fibrosis, 4=cirrhosis.
  • Part 1: Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages Regardless of Effect on Steatohepatitis at Month 12 [ Time Frame: Month 12 ]
    Fibrosis stage was evaluated using the NASH CRN Fibrosis Staging System with stages 0=none, 1=perisinusoidal or periportal, 1A=mild, zone 3, perisinusoidal, 1B=moderate, zone 3, perisinusoidal, 1C=portal/periportal, 2=perisinusoidal and portal/periportal, 3=bridging fibrosis, 4=cirrhosis.
  • Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage and No Worsening of Steatohepatitis on Liver Biopsy at Month 12 in the Full Study Cohort [ Time Frame: Month 12 ]
    Fibrosis stage was evaluated using the NASH CRN Fibrosis Staging System with stages: 0=none; 1=perisinusoidal or periportal; 1A=mild, zone 3, perisinusoidal; 1B=moderate, zone 3, perisinusoidal; 1C=portal/periportal; 2=perisinusoidal and portal/periportal; 3=bridging fibrosis; 4=cirrhosis. No worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade as per scoring in relevant NAS categories. NAS is a semiquantitative scoring system based on the unweighted sum of: steatosis (0=<5% to 3=>66%), lobular inflammation (0=no foci to 3=>4 foci/200x), and hepatocellular ballooning (0=none to 2=many cells/prominent ballooning) scores. Improvement in fibrosis is a decrease in the NASH CRN fibrosis stage.
  • Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage Regardless of Effect on Steatohepatitis on Liver Biopsy at Month 12 in the Full Study Cohort [ Time Frame: Month 12 ]
    Fibrosis stage was evaluated using the NASH CRN Fibrosis Staging System with stages 0=none, 1=perisinusoidal or periportal, 1A=mild, zone 3, perisinusoidal, 1B=moderate, zone 3, perisinusoidal, 1C=portal/periportal, 2=perisinusoidal and portal/periportal, 3=bridging fibrosis, 4=cirrhosis.
  • Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages and No Worsening of Steatohepatitis on Liver Biopsy at Month 12 in the Full Study Cohort [ Time Frame: Month 12 ]
    Fibrosis stage was evaluated using the NASH CRN Fibrosis Staging System with stages: 0=none; 1=perisinusoidal or periportal; 1A=mild, zone 3, perisinusoidal; 1B=moderate, zone 3, perisinusoidal; 1C=portal/periportal; 2=perisinusoidal and portal/periportal; 3=bridging fibrosis; 4=cirrhosis. No worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade as per scoring in relevant NAS categories. NAS is a semiquantitative scoring system based on the unweighted sum of: steatosis (0=<5% to 3=>66%), lobular inflammation (0=no foci to 3=>4 foci/200x), and hepatocellular ballooning (0=none to 2=many cells/prominent ballooning) scores. Improvement in fibrosis is a decrease in the NASH CRN fibrosis stage.
  • Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages Regardless of Effect on Steatohepatitis on Liver Biopsy at Month 12 in the Full Study Cohort [ Time Frame: Month 12 ]
    Fibrosis stage was evaluated using the NASH CRN Fibrosis Staging System with stages 0=none, 1=perisinusoidal or periportal, 1A=mild, zone 3, perisinusoidal, 1B=moderate, zone 3, perisinusoidal, 1C=portal/periportal, 2=perisinusoidal and portal/periportal, 3=bridging fibrosis, 4=cirrhosis.
  • Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage and No Worsening of Steatohepatitis on Liver Biopsy at Month 60 in the Full Study Cohort [ Time Frame: Month 60 ]
    Fibrosis stage was evaluated using the NASH CRN Fibrosis Staging System with stages: 0=none; 1=perisinusoidal or periportal; 1A=mild, zone 3, perisinusoidal; 1B=moderate, zone 3, perisinusoidal; 1C=portal/periportal; 2=perisinusoidal and portal/periportal; 3=bridging fibrosis; 4=cirrhosis. No worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade as per scoring in relevant NAS categories. NAS is a semiquantitative scoring system based on the unweighted sum of: steatosis (0=<5% to 3=>66%), lobular inflammation (0=no foci to 3=>4 foci/200x), and hepatocellular ballooning (0=none to 2=many cells/prominent ballooning) scores. Improvement in fibrosis is a decrease in the NASH CRN fibrosis stage.
  • Percentage of Participants With Improvement in Fibrosis by at Least 1 Stage Regardless of Effect on Steatohepatitis on Liver Biopsy at Month 60 in the Full Study Cohort [ Time Frame: Month 60 ]
    Fibrosis stage was evaluated using the NASH CRN Fibrosis Staging System with stages 0=none, 1=perisinusoidal or periportal, 1A=mild, zone 3, perisinusoidal, 1B=moderate, zone 3, perisinusoidal, 1C=portal/periportal, 2=perisinusoidal and portal/periportal, 3=bridging fibrosis, 4=cirrhosis.
  • Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages and No Worsening of Steatohepatitis on Liver Biopsy at Month 60 in the Full Study Cohort [ Time Frame: Month 60 ]
    Fibrosis stage was evaluated using the NASH CRN Fibrosis Staging System with stages: 0=none; 1=perisinusoidal or periportal; 1A=mild, zone 3, perisinusoidal; 1B=moderate, zone 3, perisinusoidal; 1C=portal/periportal; 2=perisinusoidal and portal/periportal; 3=bridging fibrosis; 4=cirrhosis. No worsening of steatohepatitis was defined as no worsening of lobular inflammation or hepatocellular ballooning grade as per scoring in relevant NAS categories. NAS is a semiquantitative scoring system based on the unweighted sum of: steatosis (0=<5% to 3=>66%), lobular inflammation (0=no foci to 3=>4 foci/200x), and hepatocellular ballooning (0=none to 2=many cells/prominent ballooning) scores. Improvement in fibrosis is a decrease in the NASH CRN fibrosis stage.
  • Percentage of Participants With Improvement in Fibrosis by at Least 2 Stages Regardless of Effect on Steatohepatitis on Liver Biopsy at Month 60 in the Full Study Cohort [ Time Frame: Month 60 ]
    Fibrosis stage was evaluated using NASH CRN Fibrosis Staging System with stages 0=None, 1=Perisinusoidal or periportal, 1A=Mild, zone 3, perisinusoidal, 1B=Moderate, zone 3, perisinusoidal, 1C=Portal/periportal, 2=Perisinusoidal and portal/periportal, 3=Bridging fibrosis, 4=Cirrhosis.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 18, 2017)
Effect of CVC compared to placebo on liver histology at Month 60 relative to the Screening biopsy for the proportion of subjects with improvement in fibrosis by at least 1 stage AND no worsening of steatohepatitis [ Time Frame: Time to accrue a pre-specified number of adjudicated events, End of Study, estimated to be 5 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE AURORA: A Study for the Efficacy and Safety of Cenicriviroc (CVC) for the Treatment of Liver Fibrosis in Adults With Nonalcoholic Steatohepatitis (NASH)
Official Title  ICMJE AURORA: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Cenicriviroc for the Treatment of Liver Fibrosis in Adult Subjects With Nonalcoholic Steatohepatitis
Brief Summary The AURORA study will be conducted to confirm the efficacy and safety of cenicriviroc (CVC) for the treatment of liver fibrosis in adult participants with NASH.
Detailed Description The AURORA study will be conducted in 2 parts. Part 1 will examine the surrogate endpoint of improvement in fibrosis of at least 1 stage (nonalcoholic steatohepatitis clinical research network [NASH CRN]) and no worsening of steatohepatitis at Month 12. Participants from Part 1 will continue into Part 2 and additional participants will be newly randomized in Part 2 to determine long-term clinical outcomes composed of histopathologic progression to cirrhosis, liver-related clinical outcomes, and all-cause mortality.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Nonalcoholic Steatohepatitis
Intervention  ICMJE
  • Drug: Placebo
    Cenicriviroc placebo-matching, tablet, orally, once daily for up to approximately 40 months.
  • Drug: Cenicriviroc
    Cenicriviroc, 150 mg, tablet, orally, once daily for up to approximately 40 months.
    Other Name: CVC
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    Participants received cenicriviroc placebo-matching, tablet, orally, once daily for up to approximately 40 months.
    Intervention: Drug: Placebo
  • Experimental: Cenicriviroc 150 mg
    Participants received cenicriviroc, 150 milligrams (mg), tablet, orally, once daily for up to approximately 40 months.
    Intervention: Drug: Cenicriviroc
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: January 4, 2022)
1778
Original Estimated Enrollment  ICMJE
 (submitted: January 18, 2017)
2000
Actual Study Completion Date  ICMJE March 9, 2021
Actual Primary Completion Date January 12, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male and female participants aged between 18-75 years
  • Ability to understand and sign a written informed consent form (ICF)
  • Histological evidence of NASH based on central reading of the Screening biopsy
  • Participants included in Part 1 must have histopathological evidence of Stage 2 or 3 liver fibrosis per the NASH CRN System based on central reading of the Screening biopsy slides. Participants newly randomized in Part 2 must have histological evidence of Stage 3 liver fibrosis per the NASH CRN System, based on central reading of the Screening period biopsy slides. Historical biopsy can be used, provided the criteria listed on Item 3a above are fulfilled.
  • Females of childbearing potential and males participating in the study must agree to use at least 2 approved methods of contraception throughout the duration of the study and for 30 days after stopping study drug. Females who are postmenopausal must have documentation of cessation of menses for ≥12 months and serum follicle-stimulating hormone (FSH) ≥30 milliunits (mU)/milliliter (mL) at Screening.

Exclusion Criteria:

  • Inability to undergo a liver biopsy
  • Hepatitis B surface antigen (HBsAg) positive
  • Hepatitis C antibody (HCVAb) positive
  • Human immunodeficiency virus (HIV)-1 or HIV-2 infection
  • Prior or planned liver transplantation
  • Other known causes of chronic liver disease
  • History or presence 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
  • Aspartate transaminase (AST) >200 International units (IU)/liter (L) in males and females at Screening
  • Alanine transaminase (ALT) >250 IU/L in males and >200 IU/L in females at Screening
  • Hemoglobin A1c (HbA1c) >10% at Screening
  • Serum albumin <3.5 gram (g)/deciliter (dL) at Screening
  • Estimated glomerular filtration rate (eGFR) < 50 mL/minute (min)/1.73 meter (m)^2 according to the Modification of Diet in Renal Disease (MDRD) equation
  • Platelet count <100,000/millimeter (mm)^3
  • Total bilirubin >1.5 milligram (mg)/dL
  • International normalized ratio (INR) >1.3
  • Model of end stage liver disease (MELD) score >12
  • Weight reduction, defined as ≥7% of body weight, through bariatric surgery in the past 5 years or bariatric surgery planned during the conduct of the study (including gastric banding and sleeve surgery)
  • History of malignancy within the past 5 years or ongoing malignancy other than basal cell carcinoma, or resected noninvasive cutaneous squamous cell carcinoma
  • Active, serious infections that require parenteral antibiotic or antifungal therapy within 30 days prior to Screening Visit
  • Clinically significant cardiovascular or cerebrovascular disease within the past 3 months
  • Females who are pregnant or breastfeeding
  • Current or anticipated treatment with radiation therapy, cytotoxic chemotherapeutic agents and immunomodulating agents (eg, interleukins, interferons, cyclosporine, tacrolimus) except for vaccines or short-term corticosteroids
  • Receiving a glucagon-like peptide 1 (GLP-1) receptor agonist, a dipeptidyl peptidase 4 (DPP-4) inhibitor, a sodium-glucose cotransporter 2 (SGLT2) and/or sodium-glucose cotransporter (SGLT1) inhibitor, or a thiazolidinedione (TZD) for less than 6 months prior to the Screening period liver biopsy. Participants on a stable therapy with a GLP-1 receptor agonist, DPP-4 inhibitor, SGLT1 and/or SGLT2 inhibitor, or a TZD for at least 6 months prior to the Screening liver biopsy may be considered eligible. (Important Note: if a historical biopsy is to be used, participants need to be on stable therapy for at least 6 months prior to the day historical liver biopsy was performed).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Belgium,   Brazil,   Canada,   Chile,   France,   Germany,   Greece,   Hong Kong,   Hungary,   Israel,   Italy,   Latvia,   Mexico,   New Zealand,   Norway,   Poland,   Portugal,   Puerto Rico,   Romania,   Russian Federation,   Singapore,   Spain,   Switzerland,   Taiwan,   United Kingdom,   United States
Removed Location Countries Argentina,   Georgia,   India,   Peru,   Slovenia
 
Administrative Information
NCT Number  ICMJE NCT03028740
Other Study ID Numbers  ICMJE 3152-301-002
2016-004566-26 ( EudraCT Number )
1001 ( Registry Identifier: Registro Nacional Estudios Clinicos (RNEC) )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Tobira Therapeutics, Inc.
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Tobira Therapeutics, Inc.
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Gerardo Rodriguez Allergan
PRS Account Tobira Therapeutics, Inc.
Verification Date November 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP