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 J.; Rinella, Mary E.; Charlton, Michael; Loomba, Rohit; Ratziu, Vlad; Kochuparampil, Jossy; Fischer, Laurent; Vaidyanathan, Sujata; Anstee, Quentin M.

doi:10.1016/j.cct.2019.105889

Cited by 89 publications

(69 citation statements)

References 42 publications

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“…In that context, combining drugs with a different mechanism of action aiming at obtaining an additive or even synergistic effect, is attractive. A few combination treatments are investigated although the efficacy of the individual treatment has not always been established [68][69][70]. In such context, lanifibranor has hence theoritically an advantage as it targets all of the 3 PPAR isotypes compared to single or dual agonists.…”

Section: Discussionmentioning

confidence: 99%

A randomised, double-blind, placebo-controlled, multi-centre, dose-range, proof-of-concept, 24-week treatment study of lanifibranor in adult subjects with non-alcoholic steatohepatitis: Design of the NATIVE study

Bédossa

et al. 2020

Contemporary Clinical Trials

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Background Non-alcoholic steatohepatitis (NASH), a multifactorial disease, can progress to hepatic fibrosis and cirrhosis. The Peroxysomal Proliferator-Activated Receptors, PPARα, β/δ and γ, play a central role in the regulation of glucose and lipid metabolism and of the inflammatory and fibrogenic pathways in liver and in other organs that all contribute to NASH pathogenesis. Lanifibranor (IVA337), a panPPAR agonist, by acting on these three different PPAR isotypes, combines pharmacological effects that could address the different components of the disease as demonstrated in preclinical models. Objectives NATIVE study (EudraCT: 2016-001979-70, NCT: NCT03008070) aims to assess the safety and the efficacy of a 24-week treatment with lanifibranor (800 and 1200 mg/day) in adult non-cirrhotic NASH patients. The primary efficacy endpoint is a 2-point reduction in the activity part of the Steatosis Activity Fibrosis (SAF) histological score (combining inflammation and ballooning) without worsening of fibrosis. Design NATIVE is a Phase 2b randomised, placebo-controlled, double-blind, parallel-assignment, dose-range study. Eligible adult patients with a confirmed histological diagnosis of NASH should have a SAF Activity score of 3 or 4 (> 2) and a SAF Steatosis score ≥ 1. There is no specific criterion related to the fibrosis score except that patients with cirrhosis (F4) were excluded. Summary This study will evaluate the efficacy of a 24-week treatment of NASH with lanifibranor based on histological evaluations (SAF score) by biopsy. The number of responders according to the SAF Activity score-based definition from baseline to 24 weeks will be compared between groups and serves as primary endpoint.

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Section: Discussionmentioning

confidence: 99%

A randomised, double-blind, placebo-controlled, multi-centre, dose-range, proof-of-concept, 24-week treatment study of lanifibranor in adult subjects with non-alcoholic steatohepatitis: Design of the NATIVE study

Bédossa

et al. 2020

Contemporary Clinical Trials

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“…In a murine model, tropifexor reversed established fibrosis and reduced the NAFLD activity score, hepatic triglycerides, and profibrogenic gene expression[ 187 ]. Currently, at least three clinical trials are evaluating the safety, tolerability, and efficacy of different doses of tropifexor in NASH patients[ 188 - 190 ].…”

Section: Management Of Liver Fibrosis In Nafldmentioning

confidence: 99%

Clinical assessment and management of liver fibrosis in non-alcoholic fatty liver disease

Campos-Murguía

Ruiz-Margáin

González-Regueiro

et al. 2020

WJG

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Non-alcoholic fatty liver disease (NAFLD) is among the most frequent etiologies of cirrhosis worldwide, and it is associated with features of metabolic syndrome; the key factor influencing its prognosis is the progression of liver fibrosis. This review aimed to propose a practical and stepwise approach to the evaluation and management of liver fibrosis in patients with NAFLD, analyzing the currently available literature. In the assessment of NAFLD patients, it is important to identify clinical, genetic, and environmental determinants of fibrosis development and its progression. To properly detect fibrosis, it is important to take into account the available methods and their supporting scientific evidence to guide the approach and the sequential selection of the best available biochemical scores, followed by a complementary imaging study (transient elastography, magnetic resonance elastography or acoustic radiation force impulse) and finally a liver biopsy, when needed. To help with the selection of the most appropriate method a Fagan′s nomogram analysis is provided in this review, describing the diagnostic yield of each method and their post-test probability of detecting liver fibrosis. Finally, treatment should always include diet and exercise, as well as controlling the components of the metabolic syndrome, +/- vitamin E, considering the presence of sleep apnea, and when available, allocate those patients with advanced fibrosis or high risk of progression into clinical trials. The final end of this approach should be to establish an opportune diagnosis and treatment of liver fibrosis in patients with NAFLD, aiming to decrease/stop its progression and improve their prognosis.

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“…The combination of tropifexor and cenicriviroc has shown promise in animal models of NASH, where it led to improvements in inflammation and histology [ 114 ]. A phase 2 randomized, double-blind, multicenter trial is underway to determine the efficacy of tropifexor and cenicriviroc in human subjects with NASH [ 115 ]. In light of the positive effects on both NASH and inflammatory markers, there is hope for concurrent effects of the combination of tropifexor and cenicriviroc in AF patients.…”

Section: Potential Therapies Targeting Nafld and Afmentioning

confidence: 99%

Nonalcoholic fatty liver disease and atrial fibrillation: possible pathophysiological links and therapeutic interventions

Haghbin

Gangwani

Ravi

et al. 2020

aog

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Atrial fibrillation (AF) and nonalcoholic fatty liver disease (NAFLD) share common risk factors and appear to have an association. Independently, the incidence and prevalence of both diseases are on the rise. Epidemiological evidence, experimental studies and various randomized clinical trials suggest a link between the 2 entities, delineating cumulative risks and clinical strategies to improve outcomes. Dyslipidemia, insulin resistance, inflammatory milieu, and activation of the renin-angiotensin system are likely common pathophysiological mechanisms linking AF and NAFLD. In this article we review the known pathways and pathophysiology that link the 2 conditions. This review also discusses therapies that target both NAFLD and AF, such as angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, statins, metformin, and vitamin E. We further discuss other potential medications that have shown effects in NAFLD or AF through anti-inflammatory, antidiabetic, lipid-lowering, or renin-angiotensin system inhibiting effects. Future epidemiological studies are needed to establish a direct causal relationship between NAFLD and AF.

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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

Cited by 89 publications

References 42 publications

A randomised, double-blind, placebo-controlled, multi-centre, dose-range, proof-of-concept, 24-week treatment study of lanifibranor in adult subjects with non-alcoholic steatohepatitis: Design of the NATIVE study

A randomised, double-blind, placebo-controlled, multi-centre, dose-range, proof-of-concept, 24-week treatment study of lanifibranor in adult subjects with non-alcoholic steatohepatitis: Design of the NATIVE study

Clinical assessment and management of liver fibrosis in non-alcoholic fatty liver disease

Nonalcoholic fatty liver disease and atrial fibrillation: possible pathophysiological links and therapeutic interventions

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