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A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.
Harrison, Stephen A; Bedossa, Pierre; Guy, Cynthia D; Schattenberg, Jörn M; Loomba, Rohit; Taub, Rebecca; Labriola, Dominic; Moussa, Sam E; Neff, Guy W; Rinella, Mary E; Anstee, Quentin M; Abdelmalek, Manal F; Younossi, Zobair; Baum, Seth J; Francque, Sven; Charlton, Michael R; Newsome, Philip N; Lanthier, Nicolas; Schiefke, Ingolf; Mangia, Alessandra; Pericàs, Juan M; Patil, Rashmee; Sanyal, Arun J; Noureddin, Mazen; Bansal, Meena B; Alkhouri, Naim; Castera, Laurent; Rudraraju, Madhavi; Ratziu, Vlad.
Affiliation
  • Harrison SA; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Bedossa P; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Guy CD; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Schattenberg JM; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Loomba R; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Taub R; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Labriola D; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Moussa SE; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Neff GW; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Rinella ME; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Anstee QM; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Abdelmalek MF; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Younossi Z; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Baum SJ; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Francque S; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Charlton MR; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Newsome PN; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Lanthier N; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Schiefke I; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Mangia A; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Pericàs JM; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Patil R; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Sanyal AJ; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Noureddin M; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Bansal MB; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Alkhouri N; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Castera L; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Rudraraju M; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
  • Ratziu V; From the University of Oxford, Oxford (S.A.H.), the Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne (Q.M.A.), and the National Institute for Health Research, Biomedical Research Centre at University Hospitals Birmingham NHS Founda
N Engl J Med ; 390(6): 497-509, 2024 02 08.
Article in En | MEDLINE | ID: mdl-38324483
ABSTRACT

BACKGROUND:

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta-selective agonist in development for the treatment of NASH with liver fibrosis.

METHODS:

We are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 111 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The two primary end points at week 52 were NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score.

RESULTS:

Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was -13.6% in the 80-mg resmetirom group and -16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group.

CONCLUSIONS:

Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage. (Funded by Madrigal Pharmaceuticals; MAESTRO-NASH ClinicalTrials.gov number, NCT03900429.).
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyridazines / Uracil / Non-alcoholic Fatty Liver Disease / Liver Cirrhosis Type of study: Clinical_trials / Etiology_studies Limits: Adult / Humans Language: En Journal: N Engl J Med Year: 2024 Type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyridazines / Uracil / Non-alcoholic Fatty Liver Disease / Liver Cirrhosis Type of study: Clinical_trials / Etiology_studies Limits: Adult / Humans Language: En Journal: N Engl J Med Year: 2024 Type: Article