A randomized, double-blind, multicenter, phase 2b study to evaluate the safety and efficacy of a combination of tropifexor and cenicriviroc in patients with nonalcoholic steatohepatitis and liver fibrosis: Study design of the TANDEM trial

Contemp Clin Trials. 2020 Jan;88:105889. doi: 10.1016/j.cct.2019.105889. Epub 2019 Nov 13.

Abstract

Background: Nonalcoholic steatohepatitis (NASH) is a multifactorial disease involving different contributing mechanisms, with no approved therapies so far. Tropifexor (TXR), a farnesoid X receptor agonist, and cenicriviroc (CVC), a chemokine receptor types 2/5 antagonist, target the steatotic, inflammatory, and/or fibrotic pathways involved in NASH.

Design: TANDEM (CLJC242A2201J; NCT03517540) is a 48-week, phase 2b, randomized, double-blind, multicenter study in 200 adult patients with biopsy-proven NASH and liver fibrosis. Patients will be randomized in a 1:1:1:1 ratio to receive either TXR 140 μg once daily (qd), CVC 150 mg qd, TXR 140 μg + CVC 150 mg qd, or TXR 90 μg + CVC 150 mg qd. The study comprises a 48-week treatment period and 4 weeks of follow-up. The key inclusion criterion is presence of NASH with fibrosis stage F2/F3 as seen on screening liver biopsy or on historical liver biopsy performed within 6 months prior to screening.

Objectives: The primary objective is evaluation of the safety and tolerability of combination therapy compared with the monotherapies over 48 weeks. The secondary objective is to evaluate efficacy as assessed by ≥1-point improvement in liver fibrosis versus baseline or resolution of steatohepatitis after 48 weeks.

Summary: TANDEM will evaluate the combination of TXR and CVC with respect to safety and efficacy outcomes related to improvement in fibrosis or resolution of steatohepatitis. Given the effects of TXR and CVC in multiple pathophysiological pathways associated with NASH, combination therapy is likely to show additional benefits compared with monotherapy.

Keywords: C-C chemokine receptors type 2 and 5; Cenicriviroc; Farnesoid X receptor; Liver fibrosis; Nonalcoholic steatohepatitis; Tropifexor.

Publication types

  • Clinical Trial Protocol
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzothiazoles / therapeutic use*
  • CCR5 Receptor Antagonists / therapeutic use*
  • Clinical Trials, Phase II as Topic
  • Double-Blind Method
  • Drug Therapy, Combination
  • Humans
  • Imidazoles / therapeutic use*
  • Isoxazoles / therapeutic use*
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / pathology
  • Multicenter Studies as Topic
  • Non-alcoholic Fatty Liver Disease / drug therapy*
  • Non-alcoholic Fatty Liver Disease / pathology
  • Randomized Controlled Trials as Topic
  • Receptors, CCR2 / antagonists & inhibitors
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Sulfoxides / therapeutic use*
  • Treatment Outcome

Substances

  • Benzothiazoles
  • CCR5 Receptor Antagonists
  • Imidazoles
  • Isoxazoles
  • Receptors, CCR2
  • Receptors, Cytoplasmic and Nuclear
  • Sulfoxides
  • farnesoid X-activated receptor
  • cenicriviroc
  • tropifexor

Associated data

  • ClinicalTrials.gov/NCT03517540