Improvements of Fibrosis and Disease Activity Are Associated With Improvement of Patient-Reported Outcomes in Patients With Advanced Fibrosis Due to Nonalcoholic Steatohepatitis

Zobair M. Younossi; Maria Stepanova; Mazen Noureddin; Kris V. Kowdley; Simone I. Strasser; Anita Kohli; Peter Ruane; Mitchell L. Shiffman; Aasim Sheikh; Nadege Gunn; Stephen H. Caldwell; Ryan S. Huss; Robert P. Myers; Vincent Wai-Sun Wong; Naim Alkhouri; Zachary Goodman; Rohit Loomba

doi:10.1002/hep4.1710

Improvements of Fibrosis and Disease Activity Are Associated With Improvement of Patient-Reported Outcomes in Patients With Advanced Fibrosis Due to Nonalcoholic Steatohepatitis

Zobair M. Younossi, Maria Stepanova, Mazen Noureddin, Kris V. Kowdley, Simone I. Strasser, Anita Kohli, Peter Ruane, Mitchell L. Shiffman, Aasim Sheikh, Nadege Gunn, Stephen H. Caldwell, Ryan S. Huss, Robert P. Myers, Vincent Wai-Sun Wong, Naim Alkhouri, Zachary Goodman, Rohit Loomba

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

Patient-reported outcomes (PROs) are important endpoints for clinical trials. The impact of investigational drugs on PROs of patients with advanced nonalcoholic steatohepatitis (NASH) was investigated. Patients with NASH with bridging fibrosis or compensated cirrhosis were enrolled in a phase 2, randomized, placebo-controlled study of selonsertib, firsocostat, or cilofexor, alone or in two-drug combinations (NCT03449446). PROs included Short Form 36 (SF-36), Chronic Liver Disease Questionnaire (CLDQ)-NASH, EuroQol Five Dimension (EQ-5D), Work Productivity and Impairment (WPAI), and 5-D Itch before and during treatment. A total of 392 patients with NASH (mean ± SD, 60 ± 9 years old; 35% men; 89% white; 72% diabetes; and 56% compensated cirrhosis) were included. Baseline Physical Functioning (PF) and Bodily Pain of SF-36 and Fatigue and Worry of CLDQ-NASH were significantly lower in patients with cirrhosis (total CLDQ-NASH score mean ± SD, 4.91 ± 1.06 with cirrhosis vs. 5.16 ± 1.14 without cirrhosis; P < 0.05). Lower baseline PRO scores were independently associated with age, female sex, greater body mass index, diabetes, clinically overt fatigue, and comorbidities (all P < 0.05). After 48 weeks of treatment, patients with ≥1-stage fibrosis improvement without worsening of NASH experienced improvement in EQ-5D and five out of six CLDQ-NASH domains (P < 0.05). Patients with ≥2-point decrease in their nonalcoholic fatty liver disease activity score (NAS) also had improvements in PF and Role Physical scores and all domains of CLDQ-NASH (P < 0.05). Progression to cirrhosis was associated with a decrease in PF scores of SF-36 (P ≤ 0.05). Fibrosis regression was independently associated with greater improvements in PF and EQ-5D scores, while NAS improvement was associated with improvement in fatigue and pruritus (all P < 0.05). Conclusion: Patients with advanced NASH experienced improvement in their PROs after fibrosis regression or improvement in disease activity.

Original language	English (US)
Pages (from-to)	1201-1211
Number of pages	11
Journal	Hepatology Communications
Volume	5
Issue number	7
DOIs	https://doi.org/10.1002/hep4.1710
State	Published - Jul 2021

ASJC Scopus subject areas

Hepatology

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10.1002/hep4.1710

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Younossi, Z. M., Stepanova, M., Noureddin, M., Kowdley, K. V., Strasser, S. I., Kohli, A., Ruane, P., Shiffman, M. L., Sheikh, A., Gunn, N., Caldwell, S. H., Huss, R. S., Myers, R. P., Wai-Sun Wong, V., Alkhouri, N., Goodman, Z., & Loomba, R. (2021). Improvements of Fibrosis and Disease Activity Are Associated With Improvement of Patient-Reported Outcomes in Patients With Advanced Fibrosis Due to Nonalcoholic Steatohepatitis. Hepatology Communications, 5(7), 1201-1211. https://doi.org/10.1002/hep4.1710

Improvements of Fibrosis and Disease Activity Are Associated With Improvement of Patient-Reported Outcomes in Patients With Advanced Fibrosis Due to Nonalcoholic Steatohepatitis. / Younossi, Zobair M.; Stepanova, Maria; Noureddin, Mazen et al.
In: Hepatology Communications, Vol. 5, No. 7, 07.2021, p. 1201-1211.

Research output: Contribution to journal › Article › peer-review

Younossi, ZM, Stepanova, M, Noureddin, M, Kowdley, KV, Strasser, SI, Kohli, A, Ruane, P, Shiffman, ML, Sheikh, A, Gunn, N, Caldwell, SH, Huss, RS, Myers, RP, Wai-Sun Wong, V, Alkhouri, N, Goodman, Z & Loomba, R 2021, 'Improvements of Fibrosis and Disease Activity Are Associated With Improvement of Patient-Reported Outcomes in Patients With Advanced Fibrosis Due to Nonalcoholic Steatohepatitis', Hepatology Communications, vol. 5, no. 7, pp. 1201-1211. https://doi.org/10.1002/hep4.1710

@article{313cbcb693d34c8184659934fd79bd07,

title = "Improvements of Fibrosis and Disease Activity Are Associated With Improvement of Patient-Reported Outcomes in Patients With Advanced Fibrosis Due to Nonalcoholic Steatohepatitis",

abstract = "Patient-reported outcomes (PROs) are important endpoints for clinical trials. The impact of investigational drugs on PROs of patients with advanced nonalcoholic steatohepatitis (NASH) was investigated. Patients with NASH with bridging fibrosis or compensated cirrhosis were enrolled in a phase 2, randomized, placebo-controlled study of selonsertib, firsocostat, or cilofexor, alone or in two-drug combinations (NCT03449446). PROs included Short Form 36 (SF-36), Chronic Liver Disease Questionnaire (CLDQ)-NASH, EuroQol Five Dimension (EQ-5D), Work Productivity and Impairment (WPAI), and 5-D Itch before and during treatment. A total of 392 patients with NASH (mean ± SD, 60 ± 9 years old; 35% men; 89% white; 72% diabetes; and 56% compensated cirrhosis) were included. Baseline Physical Functioning (PF) and Bodily Pain of SF-36 and Fatigue and Worry of CLDQ-NASH were significantly lower in patients with cirrhosis (total CLDQ-NASH score mean ± SD, 4.91 ± 1.06 with cirrhosis vs. 5.16 ± 1.14 without cirrhosis; P < 0.05). Lower baseline PRO scores were independently associated with age, female sex, greater body mass index, diabetes, clinically overt fatigue, and comorbidities (all P < 0.05). After 48 weeks of treatment, patients with ≥1-stage fibrosis improvement without worsening of NASH experienced improvement in EQ-5D and five out of six CLDQ-NASH domains (P < 0.05). Patients with ≥2-point decrease in their nonalcoholic fatty liver disease activity score (NAS) also had improvements in PF and Role Physical scores and all domains of CLDQ-NASH (P < 0.05). Progression to cirrhosis was associated with a decrease in PF scores of SF-36 (P ≤ 0.05). Fibrosis regression was independently associated with greater improvements in PF and EQ-5D scores, while NAS improvement was associated with improvement in fatigue and pruritus (all P < 0.05). Conclusion: Patients with advanced NASH experienced improvement in their PROs after fibrosis regression or improvement in disease activity.",

author = "Younossi, {Zobair M.} and Maria Stepanova and Mazen Noureddin and Kowdley, {Kris V.} and Strasser, {Simone I.} and Anita Kohli and Peter Ruane and Shiffman, {Mitchell L.} and Aasim Sheikh and Nadege Gunn and Caldwell, {Stephen H.} and Huss, {Ryan S.} and Myers, {Robert P.} and {Wai-Sun Wong}, Vincent and Naim Alkhouri and Zachary Goodman and Rohit Loomba",

note = "Funding Information: Potential conflict of interest: Dr. Younossi received research funding and has served as consultant to Gilead Sciences, Intercept, Bristol Myers Squibb, NovoNordisk, Viking, Terns, Siemens, Shionogi, AbbVie, Merck, and Novartis. Dr. Kohli advises Gilead Sciences, Novartis, and Intercept; she is on the speakers{\textquoteright} bureau of Intercept; she received grants from Gilead Sciences, Novartis, Intercept, Akero, Allergan Axcella, Bristol Myers Squibb Cirius, Conatus, CymaBay, Eli Lilly, Enyo, Galectin, Genfit, HighTide, Metacrine, NGM, NorthSea, Novo Nordisk, Madrigal, Poxel, Pfizer, Prometheus, Regeneron, Terns, and Viking. Dr. Gunn received grants from Bristol Myers Squibb, Corcept, Enyo, NorthSea, 89Bio, Poxel, Genentech, Madrigal, NGM Bio, Gilead, Novo Nordisk, Axcella, CymaBay, Genfit, and HighTide; she is on the speakers{\textquoteright} bureau and teaching staff of Gilead, Dova, Salix, AbbVie, and Intercept. Dr. Strasser received honoraria for advisory board participation and is on the speakers{\textquoteright} bureau for Gilead Sciences, Roche, Astra Zeneca, Ipsen, Eisai, Bayer Healthcare, Bristol Myers Squibb, MSD, AbbVie, Norgine, Astellas, Novartis, Pfizer, CSL‐Behring, and Dr. Falk Pharma. Dr. Wong consults for and/or is an advisory board member for 3V‐BIO, AbbVie, Allergan, Boehringer Ingelheim, Center for Outcomes Research in Liver Diseases, Echosens, Gilead Sciences, Hanmi Pharmaceutical, Intercept, Merck, Novartis, Novo Nordisk, Perspectum Diagnostics, Pfizer, ProSciento, Sagimet Biosciences, TARGET PharmaSolutions, and Terns; he is on the speakers{\textquoteright} bureau for AbbVie, Bristol Myers Squibb, Echosens, and Gilead Sciences; he received grants from Gilead Sciences. Dr. Sheikh received grants from Madrigal, Gilead, and Novartis. Dr. Noureddin advises Allergan, Gilead, and Novartis; he owns stock in Anaetos and Viking; he consults for Allergan, Gilead, Novartis, 89Bio, Intercept, Pfizer, Novo Nordisk, Blade, Echosens, Fractyl, Terns, OWL, Siemens, Roche Diagnostic, and Abbott; he received grants from Viking, Bristol Myers Squibb, Galmed, Galectin, Genfit, Conatus, Enanta, Madrigal, Shire, and Zydus. Dr. Ruane advises and is on the speakers{\textquoteright} bureau for Gilead and Viiv. Dr. Loomba consults for AstraZeneca, Bristol Myers Squibb, Eli Lilly, Galmed, Gilead, Intercept, Janssen, Madrigal, NGM Biopharmaceuticals, Pfizer, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, CohBar, Glympse Bio, Inipharm, Ionis, Metacrine, Novartis, Novo Nordisk, Sagimet 89Bio, and Viking Therapeutics; he received grants from AstraZeneca, Bristol Myers Squibb, Eli Lilly, Galmed, Gilead, Intercept, Janssen, Madrigal, NGM Biopharmaceuticals, Pfizer, Allergan, Boehringer‐Ingelheim, Galectic, Genfit, Inventiva, Merck, and Siemens; he is a cofounder of Lipnexus, Inc. Dr. Kowdley consults for Altimmune, Roche, and Boeringer Inghelheim; he advises Gilead, Intercept, HighTide, Assembly, and Callidiats; he is on the speakers{\textquoteright} bureau for Gilead, Intercept, and AbbVie; he received grants from Gilead, Intercept, HighTide, Janssen, Allergan, Genfit, Novartis, Enanta, and CymaBay. Dr. Myers and Dr. Huss are employed by and own stock in Gilead. Dr. Caldwell received grants from Gilead, Bristol Myers Squibb, Galectin, Zydus, Madrigal, Akero, and Galmed; he receives royalties for Avanos. The other authors have nothing to report. Funding Information: Supported by Gilead Sciences. Publisher Copyright: {\textcopyright} 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.",

year = "2021",

month = jul,

doi = "10.1002/hep4.1710",

language = "English (US)",

volume = "5",

pages = "1201--1211",

journal = "Hepatology Communications",

issn = "2471-254X",

publisher = "Lippincott Williams and Wilkins",

number = "7",

}

TY - JOUR

T1 - Improvements of Fibrosis and Disease Activity Are Associated With Improvement of Patient-Reported Outcomes in Patients With Advanced Fibrosis Due to Nonalcoholic Steatohepatitis

AU - Younossi, Zobair M.

AU - Stepanova, Maria

AU - Noureddin, Mazen

AU - Kowdley, Kris V.

AU - Strasser, Simone I.

AU - Kohli, Anita

AU - Ruane, Peter

AU - Shiffman, Mitchell L.

AU - Sheikh, Aasim

AU - Gunn, Nadege

AU - Caldwell, Stephen H.

AU - Huss, Ryan S.

AU - Myers, Robert P.

AU - Wai-Sun Wong, Vincent

AU - Alkhouri, Naim

AU - Goodman, Zachary

AU - Loomba, Rohit

N1 - Funding Information: Potential conflict of interest: Dr. Younossi received research funding and has served as consultant to Gilead Sciences, Intercept, Bristol Myers Squibb, NovoNordisk, Viking, Terns, Siemens, Shionogi, AbbVie, Merck, and Novartis. Dr. Kohli advises Gilead Sciences, Novartis, and Intercept; she is on the speakers’ bureau of Intercept; she received grants from Gilead Sciences, Novartis, Intercept, Akero, Allergan Axcella, Bristol Myers Squibb Cirius, Conatus, CymaBay, Eli Lilly, Enyo, Galectin, Genfit, HighTide, Metacrine, NGM, NorthSea, Novo Nordisk, Madrigal, Poxel, Pfizer, Prometheus, Regeneron, Terns, and Viking. Dr. Gunn received grants from Bristol Myers Squibb, Corcept, Enyo, NorthSea, 89Bio, Poxel, Genentech, Madrigal, NGM Bio, Gilead, Novo Nordisk, Axcella, CymaBay, Genfit, and HighTide; she is on the speakers’ bureau and teaching staff of Gilead, Dova, Salix, AbbVie, and Intercept. Dr. Strasser received honoraria for advisory board participation and is on the speakers’ bureau for Gilead Sciences, Roche, Astra Zeneca, Ipsen, Eisai, Bayer Healthcare, Bristol Myers Squibb, MSD, AbbVie, Norgine, Astellas, Novartis, Pfizer, CSL‐Behring, and Dr. Falk Pharma. Dr. Wong consults for and/or is an advisory board member for 3V‐BIO, AbbVie, Allergan, Boehringer Ingelheim, Center for Outcomes Research in Liver Diseases, Echosens, Gilead Sciences, Hanmi Pharmaceutical, Intercept, Merck, Novartis, Novo Nordisk, Perspectum Diagnostics, Pfizer, ProSciento, Sagimet Biosciences, TARGET PharmaSolutions, and Terns; he is on the speakers’ bureau for AbbVie, Bristol Myers Squibb, Echosens, and Gilead Sciences; he received grants from Gilead Sciences. Dr. Sheikh received grants from Madrigal, Gilead, and Novartis. Dr. Noureddin advises Allergan, Gilead, and Novartis; he owns stock in Anaetos and Viking; he consults for Allergan, Gilead, Novartis, 89Bio, Intercept, Pfizer, Novo Nordisk, Blade, Echosens, Fractyl, Terns, OWL, Siemens, Roche Diagnostic, and Abbott; he received grants from Viking, Bristol Myers Squibb, Galmed, Galectin, Genfit, Conatus, Enanta, Madrigal, Shire, and Zydus. Dr. Ruane advises and is on the speakers’ bureau for Gilead and Viiv. Dr. Loomba consults for AstraZeneca, Bristol Myers Squibb, Eli Lilly, Galmed, Gilead, Intercept, Janssen, Madrigal, NGM Biopharmaceuticals, Pfizer, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, CohBar, Glympse Bio, Inipharm, Ionis, Metacrine, Novartis, Novo Nordisk, Sagimet 89Bio, and Viking Therapeutics; he received grants from AstraZeneca, Bristol Myers Squibb, Eli Lilly, Galmed, Gilead, Intercept, Janssen, Madrigal, NGM Biopharmaceuticals, Pfizer, Allergan, Boehringer‐Ingelheim, Galectic, Genfit, Inventiva, Merck, and Siemens; he is a cofounder of Lipnexus, Inc. Dr. Kowdley consults for Altimmune, Roche, and Boeringer Inghelheim; he advises Gilead, Intercept, HighTide, Assembly, and Callidiats; he is on the speakers’ bureau for Gilead, Intercept, and AbbVie; he received grants from Gilead, Intercept, HighTide, Janssen, Allergan, Genfit, Novartis, Enanta, and CymaBay. Dr. Myers and Dr. Huss are employed by and own stock in Gilead. Dr. Caldwell received grants from Gilead, Bristol Myers Squibb, Galectin, Zydus, Madrigal, Akero, and Galmed; he receives royalties for Avanos. The other authors have nothing to report. Funding Information: Supported by Gilead Sciences. Publisher Copyright: © 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.

PY - 2021/7

Y1 - 2021/7

N2 - Patient-reported outcomes (PROs) are important endpoints for clinical trials. The impact of investigational drugs on PROs of patients with advanced nonalcoholic steatohepatitis (NASH) was investigated. Patients with NASH with bridging fibrosis or compensated cirrhosis were enrolled in a phase 2, randomized, placebo-controlled study of selonsertib, firsocostat, or cilofexor, alone or in two-drug combinations (NCT03449446). PROs included Short Form 36 (SF-36), Chronic Liver Disease Questionnaire (CLDQ)-NASH, EuroQol Five Dimension (EQ-5D), Work Productivity and Impairment (WPAI), and 5-D Itch before and during treatment. A total of 392 patients with NASH (mean ± SD, 60 ± 9 years old; 35% men; 89% white; 72% diabetes; and 56% compensated cirrhosis) were included. Baseline Physical Functioning (PF) and Bodily Pain of SF-36 and Fatigue and Worry of CLDQ-NASH were significantly lower in patients with cirrhosis (total CLDQ-NASH score mean ± SD, 4.91 ± 1.06 with cirrhosis vs. 5.16 ± 1.14 without cirrhosis; P < 0.05). Lower baseline PRO scores were independently associated with age, female sex, greater body mass index, diabetes, clinically overt fatigue, and comorbidities (all P < 0.05). After 48 weeks of treatment, patients with ≥1-stage fibrosis improvement without worsening of NASH experienced improvement in EQ-5D and five out of six CLDQ-NASH domains (P < 0.05). Patients with ≥2-point decrease in their nonalcoholic fatty liver disease activity score (NAS) also had improvements in PF and Role Physical scores and all domains of CLDQ-NASH (P < 0.05). Progression to cirrhosis was associated with a decrease in PF scores of SF-36 (P ≤ 0.05). Fibrosis regression was independently associated with greater improvements in PF and EQ-5D scores, while NAS improvement was associated with improvement in fatigue and pruritus (all P < 0.05). Conclusion: Patients with advanced NASH experienced improvement in their PROs after fibrosis regression or improvement in disease activity.

AB - Patient-reported outcomes (PROs) are important endpoints for clinical trials. The impact of investigational drugs on PROs of patients with advanced nonalcoholic steatohepatitis (NASH) was investigated. Patients with NASH with bridging fibrosis or compensated cirrhosis were enrolled in a phase 2, randomized, placebo-controlled study of selonsertib, firsocostat, or cilofexor, alone or in two-drug combinations (NCT03449446). PROs included Short Form 36 (SF-36), Chronic Liver Disease Questionnaire (CLDQ)-NASH, EuroQol Five Dimension (EQ-5D), Work Productivity and Impairment (WPAI), and 5-D Itch before and during treatment. A total of 392 patients with NASH (mean ± SD, 60 ± 9 years old; 35% men; 89% white; 72% diabetes; and 56% compensated cirrhosis) were included. Baseline Physical Functioning (PF) and Bodily Pain of SF-36 and Fatigue and Worry of CLDQ-NASH were significantly lower in patients with cirrhosis (total CLDQ-NASH score mean ± SD, 4.91 ± 1.06 with cirrhosis vs. 5.16 ± 1.14 without cirrhosis; P < 0.05). Lower baseline PRO scores were independently associated with age, female sex, greater body mass index, diabetes, clinically overt fatigue, and comorbidities (all P < 0.05). After 48 weeks of treatment, patients with ≥1-stage fibrosis improvement without worsening of NASH experienced improvement in EQ-5D and five out of six CLDQ-NASH domains (P < 0.05). Patients with ≥2-point decrease in their nonalcoholic fatty liver disease activity score (NAS) also had improvements in PF and Role Physical scores and all domains of CLDQ-NASH (P < 0.05). Progression to cirrhosis was associated with a decrease in PF scores of SF-36 (P ≤ 0.05). Fibrosis regression was independently associated with greater improvements in PF and EQ-5D scores, while NAS improvement was associated with improvement in fatigue and pruritus (all P < 0.05). Conclusion: Patients with advanced NASH experienced improvement in their PROs after fibrosis regression or improvement in disease activity.

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ER -

Improvements of Fibrosis and Disease Activity Are Associated With Improvement of Patient-Reported Outcomes in Patients With Advanced Fibrosis Due to Nonalcoholic Steatohepatitis

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