Improving the fitness of the NASH clinical trial: Standardizing the standard-of-care intervention

SEE ARTICLE ON PAGE 172 NAFLD is the most common chronic liver disease worldwide, ranging in severity from simple steatosis to NASH, with NASH in particular increasing risk of mortality related to cardiovascular disease, malignancy, and cirrhosis. Prevalence of NAFLD among obese adults worldwide is 51% and relatively higher in men (59%) than women (48%).[1] A survey study showed that over the past three decades, NAFLD is the only consistently increasing liver disease in the USA, mirroring the increase in obesity and type 2 diabetes mellitus.[2] Given the high prevalence of NAFLD, increased risk of morbidity and mortality associated with NASH, and absence of approved therapies, there is an existing arms race to develop effective treatments in addition to lifestyle modification. Lifestyle modification will remain vital to managing NASH even after medical interventions become available. Lifestyle modification remains the standard of care (SOC) for NASH, with the goal of optimizing weight and insulin sensitivity. The current study in this issue of Hepatology by Stine et al. seeks to better understand the impact of exercise on the coagulation profile of patients with NASH.[3] In their randomized controlled trial (RCT), the investigators show that exercise training resulted significantly in lowering plasminogen activator inhibitor 1 (PAI‐1), an important mediator in coagulation risk. This observation ran in parallel with MRI/proton density fat fraction reduction and improvement in fitness, as measured by maximal oxygen uptake (V02 peak), using exercise testing. These results are interesting and open the door for further studies designed to understand the impact of exercise on PAI‐1 and whether, clinically, there is a decrease in thromboembolic events as a result. Outside of identifying and studying this important endpoint in patients with NASH, Stine et al. demonstrate how to masterfully conduct an exercise‐based trial and carefully describe their exercise intervention that will allow for future cross‐trial validation. Given that exercise and lifestyle changes are the SOC in the treatment of NASH, they will remain the foundation of any future pharmaceutical intervention. The randomized, double‐blind, placebo‐controlled clinical trial remains the gold standard to assess such therapies. As such, it is important to consider the effect the control group, which is lifestyle modification, will have on optimal trial design, including sample‐size calculations and definition of treatment endpoints. Given that improvement in lifestyle can have significant effects on the liver in patients with NAFLD, it may contribute to the high rate of “placebo effect” often observed in NASH drug trials. A recent systematic review and meta‐analysis of placebo groups from 39 histology‐based RCTs of adults with NASH reported that 25% of patients in the control groups (95% CI, 20–30) had an improvement in NAFLD Activity Score by >2 points, and 21% had an improved fibrosis score.[4] This high placebo response rate necessitates larger trials to guarantee sufficient power to detect any difference between placebo and intervention arms. Without clinical trial protocols providing uniform guidance on lifestyle modification deployed as the control group to better account for placebo response, there are challenges for interpreting outcomes and cross‐trial comparisons are difficult to conduct. One of many challenges in an exercise‐based study is that lifestyle modifications are impacted by a range of inputs, including personal preference, tradition, culture, religion, health beliefs and goals, economics, and environment (Figure 1). In that background is the Hawthorne effect, where patients either consciously or unconsciously alter their behavior as a response to being observed.[5] Consider the patient enrolled in a NASH study allocated to the SOC arm and disappointed to not be in the drug/intervention arm. That patient responds by increasing their exercise and improving their diet modification to account for that disappointment, and now this effect has introduced bias, which will influence outcomes. If the SOC is not well defined ahead of the study and monitored throughout, these intervention modifiers may influence outcomes. Without prospectively addressing which lifestyle recommendations were followed during a trial, a comprehensive examination of factors influencing placebo response rates is not possible. As the field of NASH continues to advance, it will need standardized tools for measuring lifestyle modification in order to better understand the effect of promising pharmaceutical interventions on the underlying pathophysiology in the context of lifestyle changes.FIGURE 1: Range of influences that confound a lifestyle modification standard‐of‐care placebo arm in NASH clinical research trialsThe current American Association for the Study of Liver Diseases and European Association for the Study of the Liver guidelines recommend weight loss, achieved by hypocaloric diets in conjunction with increased physical activity for treatment of NAFLD/NASH.[6,7] In the clinical trials that guide both recommendations for clinical care of NAFLD/NASH, as well as serve as a framework for current clinical studies, the protocol of lifestyle modification is either not captured, not well defined, or incompletely described. A review of 46 clinical trials available on PubMed and clinicaltrials.gov showed that 52% of randomized and investigator‐initiated controlled trials did not describe lifestyle modification, 22% had an undefined recommendation of diet and/or exercise, and only 26% had nutritional counseling and/or exercise recommendations.[8] In reviewing lifestyle recommendations in NASH clinical trials, three categories emerge—integrated nutritional counseling and/or exercise recommendations, undefined recommendations of diet and exercise, or no mention of diet or exercise. Without this basic information, early‐phase studies that fail to demonstrate a therapeutic response over control treatment arms deploying lifestyle recommendations may do so because of an inadequate sample size that fails to consider lifestyle changes as covariates or confounders in the outcomes of a drug intervention. The current study included patients with biopsy‐proven NASH completing <90 min of weekly physical activity. Patients were randomized 2:1 with exercise training and SOC, with dietary counseling provided to both arms at the onset of the study. Subjects were provided teaching from a study‐registered dietician in Mediterranean diet practices, as well as individualized caloric goals. Patients in the exercise arm underwent five supervised 30‐min moderate‐intensity (heart rate corresponding to 45%–55% of VO2 max) aerobic exercise sessions weekly, and activity was tracked using a multiaxial accelerometer. At the onset of the trial, SOC and exercise intervention were as clearly defined as the endpoints being sought, making this current work an example of how to envision the standardization of a dietary or exercise intervention in NASH clinical trials. In 2014, the Liver Forum was founded to advance the regulatory science for treatment of NASH and liver fibrosis by identifying barriers and gaps in the field. The Liver Forum Standard of Care Working Group was created to focus on inconsistent recommendations and documentation of lifestyle in NASH clinical trials and developed consensus guidance for a standardized approach to SOC.[8] By examining lessons learned from applying lifestyle recommendations to clinical trials in NASH, diabetes, and obesity, the working group provides a framework by which to design SOC in control arms of NASH clinical trials. The working group proposes a method by which to improve the scientific rigor of NASH clinical trials by standardizing SOC with the hopes of reducing potential bias. While the framework exists, flexibility is permitted as to which recommendations to use depending on many factors that take into account increased cost to both patients and sponsors. The authors of NASHFit point out that NASH and the benefit of exercise are not limited to the liver and investigate whether exercise may provide improved benefit to the hemostatic profile. They demonstrate decreased PAI‐1 in patients with NASH along with improved cardiorespiratory fitness in those patients allocated to the exercise treatment arm. Whereas the aim of this study provides a foundation for studying the clinical impact of exercise on coagulopathy in NASH, it also highlights the importance of less frequently explored cardiovascular outcomes in NASH clinical trials. Considered a vital metric of cardiovascular disease by the American Heart Association, cardiorespiratory fitness is key for any multiorgan disease primarily affected by cardiac mortality, such as NAFLD/NASH. Cardiorespiratory fitness depends on the efficacy of oxygen transport from lungs and circulation to the skeletal muscle, and its use and capacity to generate energy for kinetic movement at the subcellular level (i.e., the mitochondria) during exercise. Not surprisingly, such a complex parameter is considered a stronger predictor of overall and cardiovascular mortality than other well‐known risk factors (e.g., smoking, diabetes, and hypertension).[9] Taken together, the improvements observed on cardiovascular risk factors, such as weight, visceral adipose tissue, and glucose hemostasis, along with the improved peak VO2, speak of disease modification at the core of NASH pathogenesis. As such, even when considering that the changes facilitated by the NASHFit intervention carry uncertain clinical relevance, the combined effect of multiple benefits would expectedly translate into better clinical outcomes. By standardizing the placebo and intervention arms, the investigators create a structure by which this question can be further elucidated in studies yet to come and highlights the importance of standardizing SOC in NASH clinical trials. It remains to be determined whether other types of exercise interventions, with variations in type of workout, delivery method, intensity, or duration, would exert similar effects. Confirmatory, larger RCTs are eagerly awaited to standardize our exercise prescription in NASH. CONFLICT OF INTEREST Dr. Durate‐Rojo advises for and received grants from Axcella Health Inc. AUTHOR CONTRIBUTIONS Kappus manuscript design, analyzed data, wrote manuscript. Patel reviewed and approved final manuscript. Duarte‐Rojo reviewed and approved final manuscript.