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

Marcos Pedrosa, Star Seyedkazemi, Sven Francque, Arun Sanyal, Mary Rinella, Michael Charlton, Rohit Loomba, Vlad Ratziu, Jossy Kochuparampil, Laurent Fischer, Sujata Vaidyanathan, Quentin M. Anstee*

*Corresponding author for this work

Research output: Contribution to journalArticle

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. 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.

Original languageEnglish (US)
Article number105889
JournalContemporary Clinical Trials
Volume88
DOIs
StatePublished - Jan 2020

Fingerprint

Liver Cirrhosis
Safety
Fatty Liver
Biopsy
Fibrosis
Chemokine Receptors
Liver
Therapeutics
Double-Blind Method
Multicenter Studies
TAK-652
Non-alcoholic Fatty Liver Disease

Keywords

  • C-C chemokine receptors type 2 and 5
  • Cenicriviroc
  • Farnesoid X receptor
  • Liver fibrosis
  • Nonalcoholic steatohepatitis
  • Tropifexor

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Pedrosa, Marcos ; Seyedkazemi, Star ; Francque, Sven ; Sanyal, Arun ; Rinella, Mary ; Charlton, Michael ; Loomba, Rohit ; Ratziu, Vlad ; Kochuparampil, Jossy ; Fischer, Laurent ; Vaidyanathan, Sujata ; Anstee, Quentin M. / 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. In: Contemporary Clinical Trials. 2020 ; Vol. 88.
@article{abab9afd710b4d1e95a43b5c85281db0,
title = "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",
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. 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",
author = "Marcos Pedrosa and Star Seyedkazemi and Sven Francque and Arun Sanyal and Mary Rinella and Michael Charlton and Rohit Loomba and Vlad Ratziu and Jossy Kochuparampil and Laurent Fischer and Sujata Vaidyanathan and Anstee, {Quentin M.}",
year = "2020",
month = "1",
doi = "10.1016/j.cct.2019.105889",
language = "English (US)",
volume = "88",
journal = "Contemporary Clinical Trials",
issn = "1551-7144",
publisher = "Elsevier Inc.",

}

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. / Pedrosa, Marcos; Seyedkazemi, Star; Francque, Sven; Sanyal, Arun; Rinella, Mary; Charlton, Michael; Loomba, Rohit; Ratziu, Vlad; Kochuparampil, Jossy; Fischer, Laurent; Vaidyanathan, Sujata; Anstee, Quentin M.

In: Contemporary Clinical Trials, Vol. 88, 105889, 01.2020.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

T2 - Study design of the TANDEM trial

AU - Pedrosa, Marcos

AU - Seyedkazemi, Star

AU - Francque, Sven

AU - Sanyal, Arun

AU - Rinella, Mary

AU - Charlton, Michael

AU - Loomba, Rohit

AU - Ratziu, Vlad

AU - Kochuparampil, Jossy

AU - Fischer, Laurent

AU - Vaidyanathan, Sujata

AU - Anstee, Quentin M.

PY - 2020/1

Y1 - 2020/1

N2 - 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. 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.

AB - 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. 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.

KW - C-C chemokine receptors type 2 and 5

KW - Cenicriviroc

KW - Farnesoid X receptor

KW - Liver fibrosis

KW - Nonalcoholic steatohepatitis

KW - Tropifexor

UR - http://www.scopus.com/inward/record.url?scp=85075281743&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85075281743&partnerID=8YFLogxK

U2 - 10.1016/j.cct.2019.105889

DO - 10.1016/j.cct.2019.105889

M3 - Article

C2 - 31731005

AN - SCOPUS:85075281743

VL - 88

JO - Contemporary Clinical Trials

JF - Contemporary Clinical Trials

SN - 1551-7144

M1 - 105889

ER -