Clinical trial NCT02217475: Efficacy and Safety Study of Cenicriviroc for the Treatment of Nonalcoholic Steatohepatitis (NASH) in Adult Participants With Liver Fibrosis
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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Nonalcoholic Steatohepatitis
Lead sponsor: Tobira Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2014-08-15
Enrollment: 289
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


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):

  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.

Primary outcomes:
measure: 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
timeFrame: Year 1
Secondary outcomes:
measure: 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
timeFrame: Year 1
measure: 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
timeFrame: Year 2
measure: Number of Participants With Complete Resolution of Steatohepatitis With no Concurrent Worsening of Fibrosis Stage at Year 1
timeFrame: Year 1
measure: Number of Participants With Complete Resolution of Steatohepatitis With no Concurrent Worsening of Fibrosis Stage at Year 2
timeFrame: Year 2
measure: Number of Participants With Improvement in Fibrosis by at Least 1 Stage (NASH CRN System) and no Worsening of Steatohepatitis at Year 1
timeFrame: Year 1
measure: Number of Participants With Improvement in Fibrosis by at Least 1 Stage (NASH CRN System) and no Worsening of Steatohepatitis at Year 2
timeFrame: Year 2
measure: Number of Participants With Deaths, Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), TEAEs Leading Study Drug to Discontinuation
timeFrame: Years 1 and 2
measure: Number of Participants With Clinically Significant Changes in Vital Signs
timeFrame: Years 1 and 2
measure: Number of Participants With Clinical Laboratory Abnormalities
timeFrame: Years 1 and 2
measure: Number of Participants With Clinically Abnormal in Electrocardiogram (ECG) Findings
timeFrame: Years 1 and 2
measure: Number of Participants With Hepatic Histological Improvement in NAS at Year 2
timeFrame: Year 2
measure: Change From Baseline in the 3 Categorical Features of NAS (Steatosis, Lobular Inflammation, Hepatocellular Ballooning) at Year 1
timeFrame: Year 1
measure: Change From Baseline in the 3 Categorical Features of NAS (Steatosis, Lobular Inflammation, Hepatocellular Ballooning) at Year 2
timeFrame: Year 2
measure: 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
timeFrame: Year 1
measure: 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
timeFrame: Year 2
measure: 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
timeFrame: Year 1
measure: 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
timeFrame: Year 2
measure: Change From Baseline in Morphometric Quantitative Collagen on Liver Biopsy at Year 1
timeFrame: Year 1
measure: Change From Baseline in Morphometric Quantitative Collagen on Liver Biopsy at Year 2
timeFrame: Year 2
measure: Change From Baseline in Hepatic Tissue Fibrogenic Protein Alpha-Smooth Muscle Actin (α-SMA) at Year 1
timeFrame: Baseline (Day 1) to Year 1
measure: Change From Baseline in Hepatic Tissue Fibrogenic Protein Alpha-Smooth Muscle Actin (α-SMA) at Year 2
timeFrame: Baseline (Day 1) to Year 2
measure: Change From Baseline in Morphometric Quantitative Fat Content on Liver Biopsy at Year 1
timeFrame: Year 1
measure: Change From Baseline in Morphometric Quantitative Fat Content on Liver Biopsy at Year 2
timeFrame: Year 2
measure: Change From Baseline in Histologic Fibrosis Stage (NASH CRN System and Ishak Scale Score) at Year 1
timeFrame: Baseline (Day 1) to Year 1
measure: Change From Baseline in Histologic Fibrosis Stage (NASH CRN System and Ishak Scale Score) at Year 2
timeFrame: Baseline (Day 1) to Year 2
measure: Change From Baseline in Portal Inflammation Grade on Liver Biopsy at Year 1
timeFrame: Baseline (Day 1) to Year 1
measure: Change From Baseline in Portal Inflammation Grade on Liver Biopsy at Year 2
timeFrame: Baseline (Day 1) to Year 2
measure: Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Aspartate Aminotransferase to Platelet Count Ratio Index (APRI) at Months 3, 6 and 12
timeFrame: Baseline (Month 0) to Months 3, 6 and 12
measure: Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Aspartate Aminotransferase to Platelet Count Ratio Index (APRI) at Months 15, 18 and 24
timeFrame: Baseline (Month 0) to Months 15, 18 and 24
measure: Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Fibrosis-4 (FIB-4) at Months 3, 6 and 12
timeFrame: Baseline (Month 0) to Months 3, 6 and 12
measure: Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Fibrosis-4 (FIB-4) at Months 15, 18 and 24
timeFrame: Baseline (Month 0) to Months 15, 18 and 24
measure: Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Hyaluronic Acid at Months 6 and 12
timeFrame: Baseline (Month 0) to Months 6 and 12
measure: Change From Baseline in Non-invasive Marker of Hepatic Fibrosis: Hyaluronic Acid at Months 18 and 24
timeFrame: Baseline (Month 0) to Months 18 and 24
measure: Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Nonalcoholic Fatty Liver Disease (NAFLD) Fibrosis Score (NFS) at Months 3, 6 and 12
timeFrame: Baseline (Month 0) to Months 3, 6 and 12
measure: Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: NAFLD Fibrosis Score (NFS) at Months 15, 18 and 24
timeFrame: Baseline (Month 0) to Months 15, 18 and 24
measure: Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score at Months 6 and 12
timeFrame: Baseline (Month 0) to Months 6 and 12
measure: Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score at Months 18 and 24
timeFrame: Baseline (Month 0) to Months 18 and 24
measure: 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
timeFrame: Baseline (Month 0) to Months 3, 6 and 12
measure: 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
timeFrame: Baseline (Month 0) to Months 15, 18 and 24
measure: Change From Baseline in Weight at Months 3, 6 and 12
timeFrame: Baseline (Day 1) to Months 3, 6 and 12
measure: Change From Baseline in Weight at Months 15, 18 and 24
timeFrame: Baseline (Day 1) to Months 15, 18 and 24
measure: Change From Baseline in Body Mass Index (BMI) at Months 3, 6 and 12
timeFrame: Baseline (Day 1) to Months 3, 6 and 12
measure: Change From Baseline in Body Mass Index (BMI) at Months 15, 18 and 24
timeFrame: Baseline (Day 1) to Months 15, 18 and 24
measure: Change From Baseline in Waist Circumference at Months 3, 6 and 12
timeFrame: Baseline (Day 1) to Months 3, 6 and 12
measure: Change From Baseline in Waist Circumference at Months 15, 18 and 24
timeFrame: Baseline (Day 1) to Months 15, 18 and 24
measure: Change From Baseline in Hip Circumference at Months 3, 6 and 12
timeFrame: Baseline (Day 1) to Months 3, 6 and 12
measure: Change From Baseline in Hip Circumference at Months 15, 18 and 24
timeFrame: Baseline (Day 1) to Months 15, 18 and 24
measure: Change From Baseline in Forearm Circumference at Months 3, 6 and 12
timeFrame: Baseline (Day 1) to Months 3, 6 and 12
measure: Change From Baseline in Forearm Circumference at Months 15, 18 and 24
timeFrame: Baseline (Day 1) to Months 15, 18 and 24
measure: Change From Baseline in Tricep Skinfold Thickness at Months 3, 6 and 12
timeFrame: Baseline (Day 1) to Months 3, 6 and 12
measure: Change From Baseline in Tricep Skinfold Thickness at Months 15, 18 and 24
timeFrame: Baseline (Day 1) to Months 15, 18 and 24
Other outcomes:
Locations:
city: Dothan
country: United States
state: Alabama
city: Phoenix
country: United States
state: Arizona
city: Tucson
country: United States
state: Arizona
city: Rialto
country: United States
state: California
city: San Diego
country: United States
state: California
city: San Diego
country: United States
state: California
city: San Francisco
country: United States
state: California
city: Littleton
country: United States
state: Colorado
city: Miami
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: Chicago
country: United States
state: Illinois
city: Louisville
country: United States
state: Kentucky
city: New Orleans
country: United States
state: Louisiana
city: Baltimore
country: United States
state: Maryland
city: Baltimore
country: United States
state: Maryland
city: Chevy Chase
country: United States
state: Maryland
city: Lutherville
country: United States
state: Maryland
city: Boston
country: United States
state: Massachusetts
city: Worcester
country: United States
state: Massachusetts
city: Ann Arbor
country: United States
state: Michigan
city: Saint Paul
country: United States
state: Minnesota
city: Flowood
country: United States
state: Mississippi
city: Jackson
country: United States
state: Mississippi
city: Tupelo
country: United States
state: Mississippi
city: Buffalo
country: United States
state: New York
city: New York
country: United States
state: New York
city: Durham
country: United States
state: North Carolina
city: Raleigh
country: United States
state: North Carolina
city: Winston-Salem
country: United States
state: North Carolina
city: Cincinnati
country: United States
state: Ohio
city: Chattanooga
country: United States
state: Tennessee
city: Germantown
country: United States
state: Tennessee
city: Houston
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: Live Oak
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Salt Lake City
country: United States
state: Utah
city: Richmond
country: United States
state: Virginia
city: Seattle
country: United States
state: Washington
city: Garran
country: Australia
state: Australian Capital Territory
city: Herston
country: Australia
state: Queensland
city: Adelaide
country: Australia
state: South Australia
city: Bedford Park
country: Australia
state: South Australia
city: Clayton
country: Australia
state: Victoria
city: Heidelberg
country: Australia
state: Victoria
city: Melbourne
country: Australia
state: Victoria
city: Perth
country: Australia
state: Western Australia
city: Brussels
country: Belgium
city: Brussels
country: Belgium
city: Edegem
country: Belgium
city: Leuven
country: Belgium
city: Angers
country: France
city: Lyon cedex 04
country: France
city: Montpellier Cedex 5
country: France
city: Paris
country: France
city: Paris
country: France
city: Pessac Cedex
country: France
city: Toulouse
country: France
city: Vandoeuvre-les Nancy
country: France
city: Villejuif
country: France
city: Heidelberg
country: Germany
state: BW
city: Marburg
country: Germany
state: HE
city: Hamburg
country: Germany
state: HH
city: Hannover
country: Germany
state: Niedersachsen
city: Aachen
country: Germany
state: NRW
city: Koeln
country: Germany
state: NRW
city: Leipzig
country: Germany
state: Sachsen
city: Leipzig
country: Germany
state: SN
city: Heidelberg
country: Germany
state: VIC
city: Berlin
country: Germany
city: Lubeck
country: Germany
city: Shatin
country: Hong Kong
state: New Territories
city: Bologna
country: Italy
state: BO
city: Milan
country: Italy
state: MI
city: Rozzano
country: Italy
state: MI
city: Palermo
country: Italy
state: PA
city: Chorzow
country: Poland
city: Lodz
country: Poland
city: Myslowice
country: Poland
city: Rzeszow
country: Poland
city: Wroclaw
country: Poland
city: Alicante
country: Spain
city: Barcelona
country: Spain
city: Barcelona
country: Spain
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Portsmouth
country: United Kingdom
state: Hampshire
city: London
country: United Kingdom
city: London
country: United Kingdom
city: Newcastle
country: United Kingdom
city: Nottingham
country: United Kingdom
Study officials:
affiliation: Allergan
name: Eric Lefebvre, MD
role: STUDY_DIRECTOR
References:
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.
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.
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.
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.
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.
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.