Cheng Han Ng1, Jieling Xiao1, Wen Hui Lim1, Yip Han Chin1, Jie Ning Yong1, Darren Jun Hao Tan1, Phoebe Tay1, Nicholas Syn1, Roger Foo1,2, Mark Chan1,2, Nicholas Chew1,2, Eunice Xx Tan1,3,4, Daniel Q Huang1,3,4, Yock Young Dan1,3,4, Nobuharu Tamaki5, Mohammad Shadab Siddiqui6, Arun J Sanyal7,8, Rohit Loomba5, Mazen Noureddin6, Mark D Muthiah1,3,4. 1. Yong Loo Lin School of Medicine, National University of Singapore, Singapore. 2. Department of Cardiology, National University Heart Centre, National University Hospital, Singapore. 3. Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore. 4. National University Center for Organ Transplantation, National University Health System, Singapore. 5. NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, San Diego, California, USA. 6. Cedars-Sinai Fatty Liver Program, Division of Digestive and Liver Diseases, Department of Medicine, Comprehensive Transplant Center, Cedars-Sinai Medical Centre, Los Angeles, California, USA. 7. Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, Virginia, USA. 8. Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.
Abstract
BACKGROUND AND AIMS: The evaluation of the natural history of NASH has been limited. Currently, liver biopsy remains the gold standard in the assessment of NASH. Placebo-controlled trials represent a controlled environment with paired biopsies for the evaluation of NASH. This meta-analysis thus seeks to quantify the change severity of NASH over time, with patients on placebo arms from randomized controlled trials (RCTs) to examine the natural history of NASH. METHODS: A search was conducted to include NASH RCTs with placebo treatment arms. Primary outcomes were (1) the resolution of NASH without worsening of fibrosis, (2) two-point reduction in NAFLD activity score without worsening of fibrosis, and (3) at least one-point reduction in fibrosis. Generalized linear mix model was used to estimate pooled proportion and mean differences. RESULTS: This meta-analysis of 43 RCTs included 2649 placebo-treated patients. The pooled estimate of NASH resolution and two-point NAFLD activity score reduction without worsening of fibrosis was 11.65% (95% CI: 7.98-16.71) and 21.11% (95% CI: 17.24-25.57). The rate of ≥1 stage reduction and progression of fibrosis was 18.82% (95% CI: 15.65-22.47) and 22.74% (CI: 19.63-26.17), respectively. Older age and African American ethnicity was associated with lower NASH resolution rate in placebo-treated patients. CONCLUSIONS: Despite the absence of any pharmacological interventions, a significant proportion of patients in the placebo arm demonstrated improvements in liver histology, highlighting the possibility that NASH is a disease that can not only progress but regress spontaneously over time. Additionally, histologic response in placebo-treated patients is helpful in future design of phase 2B and phase 3 trials.
BACKGROUND AND AIMS: The evaluation of the natural history of NASH has been limited. Currently, liver biopsy remains the gold standard in the assessment of NASH. Placebo-controlled trials represent a controlled environment with paired biopsies for the evaluation of NASH. This meta-analysis thus seeks to quantify the change severity of NASH over time, with patients on placebo arms from randomized controlled trials (RCTs) to examine the natural history of NASH. METHODS: A search was conducted to include NASH RCTs with placebo treatment arms. Primary outcomes were (1) the resolution of NASH without worsening of fibrosis, (2) two-point reduction in NAFLD activity score without worsening of fibrosis, and (3) at least one-point reduction in fibrosis. Generalized linear mix model was used to estimate pooled proportion and mean differences. RESULTS: This meta-analysis of 43 RCTs included 2649 placebo-treated patients. The pooled estimate of NASH resolution and two-point NAFLD activity score reduction without worsening of fibrosis was 11.65% (95% CI: 7.98-16.71) and 21.11% (95% CI: 17.24-25.57). The rate of ≥1 stage reduction and progression of fibrosis was 18.82% (95% CI: 15.65-22.47) and 22.74% (CI: 19.63-26.17), respectively. Older age and African American ethnicity was associated with lower NASH resolution rate in placebo-treated patients. CONCLUSIONS: Despite the absence of any pharmacological interventions, a significant proportion of patients in the placebo arm demonstrated improvements in liver histology, highlighting the possibility that NASH is a disease that can not only progress but regress spontaneously over time. Additionally, histologic response in placebo-treated patients is helpful in future design of phase 2B and phase 3 trials.
Authors: Jae Seung Lee; Hye Won Lee; Beom Kyung Kim; Jun Yong Park; Do Young Kim; Sang Hoon Ahn; Jae Young Jang; Soo Young Park; Hyun Woong Lee; Chun Kyon Lee; Seung Up Kim Journal: Front Med (Lausanne) Date: 2022-04-14
Authors: Nicholas W S Chew; Bryan Chong; Cheng Han Ng; Gwyneth Kong; Yip Han Chin; Wang Xiao; Mick Lee; Yock Young Dan; Mark D Muthiah; Roger Foo Journal: Front Genet Date: 2022-08-10 Impact factor: 4.772
Authors: Yip Han Chin; Cheng Han Ng; Nicholas Ws Chew; Gwyneth Kong; Wen Hui Lim; Darren Jun Hao Tan; Kai En Chan; Ansel Tang; Daniel Q Huang; Mark Y Chan; Gemma Figtree; Jiong-Wei Wang; Asim Shabbir; Chin Meng Khoo; Vincent Wai-Sun Wong; Dan Yock Young; Mohammad Shadab Siddiqui; Mazen Noureddin; Arun Sanyal; David E Cummings; Nicholas Syn; Mark Dhinesh Muthiah Journal: EClinicalMedicine Date: 2022-09-29