Rates of and Factors Associated With Placebo Response in Trials of Pharmacotherapies for Nonalcoholic Steatohepatitis: Systematic Review and Meta-analysis

Han, Ma Ai Thanda; Altayar, Osama; Hamdeh, Shadi; Takyar, Varun; Rotman, Yaron; Etzion, Ohad; Lefebvre, E.; Safadi, Rifaat; Ratziu, Vlad; Prokop, Larry J.; Murad, M. Hassan; Noureddin, Mazen

doi:10.1016/j.cgh.2018.06.011

Cited by 103 publications

(108 citation statements)

References 140 publications

(46 reference statements)

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“…While this was only a single‐arm pilot study, the positive results and low dropout rates suggest that this concept can be successfully implemented for the benefit of a patient with NAFLD. Previous meta‐analysis of placebo groups from randomised controlled trials in NASH highlighted that a placebo response can lead to reductions in BMI, transaminases and other surrogate parameters of liver injury . Albeit the absence of a control group in the current study, post hoc analysis of patients that failed to complete the predefined threshold of 70% of exercise sessions, did not show any beneficial effects.…”

Section: Discussioncontrasting

confidence: 54%

Improvement of non‐invasive markers of NAFLD from an individualised, web‐based exercise program

Huber

Pfirrmann

Gebhardt

et al. 2019

Aliment Pharmacol Ther

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Summary Background Lifestyle modifications remain the cornerstone of treatment in non‐alcoholic fatty liver disease (NAFLD). However, they requently fail related to the inability of patients to implement lasting changes. Aims To evaluate the effects of a short, web‐based, individualised exercise program on non‐invasive markers of hepatic steatosis, inflammation and fibrosis. Methods Patients with histologically confirmed NAFLD underwent an 8‐week, web‐based, individualised exercise program that contained bidirectional feedback. Results Forty‐four patients entered the study and 41 completed the assigned training goal (93.2%). In the completer population, 8 weeks of individualised exercise increased the VO2peak by 12.2% compared to baseline (P < .001). ALT and AST decreased by 14.3% (P = .002) and 18.2% (P < .001) and remained at this level until follow‐up 12 weeks after the intervention. Markers of inflammation including hsCRP, ferritin, and M30 decreased. In parallel, gut microbiota exhibited increased metagenomic richness (P < .05) and at the taxonomic levels Bacteroidetes and Euryarchaeota increased whereas Actinobacteria phylum decreased. Surrogate scores of steatosis and fibrosis including the fatty liver index (FLI), FiB‐4, APRI and transient elastography showed significant reductions. In parallel, a marker of procollagen‐3 turnover (PRO‐C3) decreased while C4M2, reflecting type IV collagen, degradation increased suggesting beneficial hepatic fibrosis remodelling from exercise. Also, an enhancement in health‐related quality of life was reported. Conclusion The current study underlines the plausibility and potential of an 8 week individualised web‐based exercise program in NAFLD. Clinical trial number: NCT02526732

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Section: Discussioncontrasting

confidence: 54%

Improvement of non‐invasive markers of NAFLD from an individualised, web‐based exercise program

Huber

Pfirrmann

Gebhardt

et al. 2019

Aliment Pharmacol Ther

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“…The current study reports an effective longitudinal histological assessment of a 12‐week therapy. To reduce the risk of unnecessary exposure of patients in the placebo group to two biopsy procedures in short succession, we conducted open‐label enrollment with a central read on slides blinded to time points and compared our results to historical placebo responses from a meta‐analysis of 39 randomized controlled trials comprising 1,463 patients with NASH . A greater proportion of patients treated with NGM282 3 mg compared with historical placebo control had improvement in fibrosis (42% versus 21%), steatosis (74% versus 33%), hepatocellular ballooning (53% versus 30%), and lobular inflammation (42% versus 32%).…”

Section: Discussionmentioning

confidence: 99%

NGM282 Improves Liver Fibrosis and Histology in 12 Weeks in Patients With Nonalcoholic Steatohepatitis

et al. 2019

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NGM282, an engineered fibroblast growth factor 19 analogue, rapidly and significantly reduced liver fat content in a multicenter, randomized, double‐blind, placebo‐controlled study in patients with biopsy‐confirmed nonalcoholic steatohepatitis (NASH). However, it is unclear whether these changes would be accompanied by histological improvement. In this open‐label study, we assessed the histological efficacy of NGM282 in patients with biopsy‐confirmed nonalcoholic steatohepatitis. Paired liver biopsies from 43 patients who received subcutaneous NGM282 (1 mg, n = 24; 3 mg, n = 19) once daily for 12 weeks were evaluated blinded to time point, subject, and clinical information. At week 12, NGM282 significantly reduced nonalcoholic fatty liver disease activity score (NAS; −1.9; 95% confidence interval, −2.6 to −1.2; P < 0.001 in the 1 mg group; −2.2, −3.1 to −1.3; P < 0.001 in the 3 mg group) and fibrosis (−0.5; −0.9 to 0; P = 0.035 in the 3 mg group) scores. Overall, 50% and 63% of the patients receiving NGM282 1 mg or 3 mg, respectively, improved NAS by 2 or more points without fibrosis worsening. Of the patients receiving NGM282 1 mg or 3 mg, 25% and 42%, respectively, improved liver fibrosis by one stage or more without worsening of steatohepatitis. Treatment with NGM282 led to relative reductions in liver fat content (−58% and −67% in the 1 mg and 3 mg groups, respectively), corrected T1 (cT1; −8% and −9%), alanine aminotransferase (ALT) (−67% and −60%), aspartate aminotransferase (−57% and −52%), and fibrogenesis biomarkers neoepitope‐specific N‐terminal propeptide of type III collagen (Pro‐C3; −22% and −33%) and enhanced liver fibrosis score (ELF; −3% and −6%) at week 12. Greater reductions in Pro‐C3, ELF, and cT1, but not in liver fat content, 7alpha‐hydroxy‐4‐cholesten‐3‐one, or ALT, were observed in histological responders than in nonresponders. Conclusion: In this open‐label study, NGM282 improved the histological features of NASH in 12 weeks with significant reductions in NAS and fibrosis scores, accompanied by improvements in noninvasive imaging and serum markers.

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“…According to recently published systematic reviews, histologic outcomes have been reported in 37 randomised, placebo‐controlled trials of adult patients with NASH (Table S1). Of these trials, 30 used the NAS system for assessing disease activity and fibrosis.…”

Section: Methodsmentioning

confidence: 99%

Standardising the interpretation of liver biopsies in non‐alcoholic fatty liver disease clinical trials

Pai¹,

Kleiner²,

Hart³

et al. 2019

Aliment Pharmacol Ther

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Summary Background There is substantial variation in how histologic definitions and scoring systems of non‐alcoholic fatty liver disease (NAFLD) are operationalised. Aim To develop a consensus‐based framework for standardising histologic assessment of liver biopsies in clinical trials of NAFLD. Methods An expert panel of 14 liver pathologists and three hepatologists was assembled. Using modified RAND/University of California Los Angeles appropriateness methodology, 130 items derived from literature review and expert opinion were rated by each panel member on a 1‐9 scale. Disagreement was defined as ≥5 ratings in the lowest (1‐3) and highest (7‐9) categories. Items were classified as inappropriate (median 1‐3.5 without disagreement), uncertain (median 3.5‐6.5 or any median with disagreement) or appropriate (median 6.5‐9 without disagreement). Survey results were discussed as a group before voting. Results Current measures of disease activity and fibrosis may not fully capture important features of non‐alcoholic steatohepatitis (NASH). Alternative methods to evaluate ballooning degeneration are needed. Panellists were uncertain whether portal inflammation, degree of steatosis and Mallory‐Denk bodies are important measures of disease activity. Furthermore, it was felt that current staging systems do not capture the full spectrum of fibrosis in NASH. A consensus definition and sub‐stages for bridging fibrosis are needed. The severity of perisinusoidal fibrosis should be captured at all stages. Lastly, a method to evaluate features of fibrosis regression should be developed. Conclusion The operating properties of the modifications proposed should be evaluated prospectively to determine reliability and responsiveness.

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Rates of and Factors Associated With Placebo Response in Trials of Pharmacotherapies for Nonalcoholic Steatohepatitis: Systematic Review and Meta-analysis

Abstract: In a meta-analysis of randomized controlled trials of NASH, patients given placebo have significant histologic, radiologic, and biochemical responses. The placebo response should be considered in designing trials of agents for treatment of NASH.

Cited by 103 publications

References 140 publications

Improvement of non‐invasive markers of NAFLD from an individualised, web‐based exercise program

Improvement of non‐invasive markers of NAFLD from an individualised, web‐based exercise program

NGM282 Improves Liver Fibrosis and Histology in 12 Weeks in Patients With Nonalcoholic Steatohepatitis

Standardising the interpretation of liver biopsies in non‐alcoholic fatty liver disease clinical trials

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