Though lifestyle modification is the standard of care for patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), the lack of standardized diet and exercise recommendations across clinical trials has limited their generalizability. The Liver Forum working group released a set of recommendations on the use of diet and exercise measures in clinical trials studying NASH. Recommendations were published in the Journal of Hepatology.
The forum conducted a systematic review of randomized, placebo-controlled trials studying patients with NAFLD/NASH. According to the working group, significant improvements in the placebo arms of some NASH studies might overshadow the beneficial effects of study drugs. Guideline authors state that lifestyle modifications – if not standardized, clearly described, or adjusted for in the study – may contribute to benefits observed in placebo groups.
The use of lifestyle recommendations in NAFLD/NASH trials is often at the discretion of study investigators. Lifestyle recommendations may also introduce recruitment and retention biases, leading to patient cohorts that are not representative of the larger NASH patient population.
Studies focusing on NASH have not systematically measured changes in either physical activity or behavior. More than half of randomized controlled trials and investigator-initiated trials have not described lifestyle modification, according to the working group’s review. Additionally, studies recommending “healthy” lifestyle changes to patients with NASH do not clearly delineate or quantify the term “healthy”, which may result in variability among recommendations. Participants in these trials may consciously or unconsciously alter their activity levels. When not adjusted for, altered activity levels may lead to outcomes among patients enrolled in clinical trials that differ from real-world patients.
The working group recommends that clinical trial participants with NASH should be assessed for current dietary and exercise habits upon screening for inclusion in studies. The working group also recommends that all patients have a stable lifestyle – including consistent weight loss and exercise programs – prior to screening to ensure baseline measures have minimal impact on lifestyle and study outcomes. Participants should also be counselled on ways to improve diet and exercise. Additionally, documentation of lifestyle measures should be performed before, at the beginning, during, and at the end of trials.
Although no current standard exists for dietary or exercise recommendations for patients with NAFLD, the working group recommends that patients should adopt interventions based on the 2016 EASL guidelines for the diagnosis and treatment of NAFLD. This guideline suggests that promoting consumption of unprocessed foods and zero-calorie beverages to patients can be helpful. The minimal physical activity recommendations of 150 to 180 minutes of moderate-intensity exercise per week should be met by all patients in clinical trials of NAFLD and NASH.
The Liver Forum working group concluded that it may be impossible or infeasible to enforce lifestyle recommendations, whether standardized or otherwise, in clinical trials. The committee instead recommends capturing data on compliance to recommendations, as this may offer “added insight and transparency by which any investigator, sponsor and/or regulatory authority can more thoughtfully ascertain and interpret study outcomes” from patients with NAFLD/NASH.
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Glass O, Filozof C, Noureddin M, et al. Standardization of diet and exercise in clinical trials of NAFLD-NASH: Recommendations from the fiver forum [published online April 27, 2020]. J Hepatol. doi: 10.1016/j.jhep.2020.04.030