A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis

Abstract

The aim of this study was to evaluate cenicriviroc (CVC), a dual antagonist of CC chemokine receptor types 2 and 5, for treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis (LF). A randomized, double-blind, multinational phase 2b study enrolled subjects with NASH, a nonalcoholic fatty liver disease activity score (NAS) ≥4, and LF (stages 1-3, NASH Clinical Research Network) at 81 clinical sites. Subjects (N = 289) were randomly assigned CVC 150 mg or placebo. Primary outcome was ≥2-point improvement in NAS and no worsening of fibrosis at year 1. Key secondary outcomes were: resolution of steatohepatitis (SH) and no worsening of fibrosis; improvement in fibrosis by ≥1 stage and no worsening of SH. Biomarkers of inflammation and adverse events were assessed. Full study recruitment was achieved. The primary endpoint of NAS improvement in the intent-to-treat population and resolution of SH was achieved in a similar proportion of subjects on CVC (N = 145) and placebo (N = 144; 16% vs. 19%, P = 0.52 and 8% vs. 6%, P = 0.49, respectively). However, the fibrosis endpoint was met in significantly more subjects on CVC than placebo (20% vs. 10%; P = 0.02). Treatment benefits were greater in those with higher disease activity and fibrosis stage at baseline. Biomarkers of systemic inflammation were reduced with CVC. Safety and tolerability of CVC were comparable to placebo.

Conclusion: After 1 year of CVC treatment, twice as many subjects achieved improvement in fibrosis and no worsening of SH compared with placebo. Given the urgent need to develop antifibrotic therapies in NASH, these findings warrant phase 3 evaluation. (Hepatology 2018;67:1754-1767).

Figure 1

Subject disposition (CONSORT flow diagram). ^aThe disposition of 4 subjects who withdrew early (1 for protocol deviation, 1 lost to follow‐up, 1 because of physician's decision, 1 other) cannot be reported in specific treatment arm as the study is ongoing and remains blinded. ^bLiver biopsy sample too small or fragmented, therefore inadequate for assessment of efficacy endpoints. ^cA subject was randomized in error without an adequate screening biopsy. Abbreviation: CONSORT, Consolidated Standards of Reporting Trials.

Figure 2

Primary endpoint and key secondary endpoint of improvement in fibrosis by ≥1 stage and no worsening of SH at year 1 (ITT analysis), with subgroup analyses for the key secondary endpoint (mITT population). (A) Subjects meeting the primary endpoint (improvement in NAS and no worsening of fibrosis). (B) Subjects meeting the key secondary endpoint of improvement in fibrosis by ≥1 stage and no worsening of SH. Missing biopsies were counted as treatment failure. (C,D,E,F) Response for the key secondary endpoint by baseline: (C) fibrosis stage (NASH CRN system); (D) fibrosis stages 2 and 3 pooled (NASH CRN system); (E) NAS stratification; and (F) hepatocellular ballooning grade. OR are presented with 95% CI and P values and were calculated using a logistic regression model with factors for randomized treatment group, NAS at screening (4 or ≥5), and fibrosis stage (≤2 or >2). Abbreviation: mITT, modified intent‐to‐treat.

Figure 3

Subgroup analyses for the key secondary endpoint of improvement in fibrosis by ≥1 stage and no worsening of SH (mITT population). Response by baseline NAS stratification, fibrosis stage (NASH CRN system), hepatocellular ballooning grade, lobular inflammation, steatosis, sex, age, BMI, T2DM, PNPLA3 genotype, and region. ^aOR and 95% CI not calculable. Abbreviations: mITT, modified intent‐to‐treat; PNPLA3, patain‐like phospholipase domain‐containing protein 3.