Diagnostic Considerations and Clinical End Points for Nonalcoholic Steatohepatitis

End points related to how a patient feels

– Quality of life

End points related to how a patient functions

– Days from work lost

– Ability to carry on day-to-day activities

End points related to how a patient survives

– Mortality

– Liver-related outcomes: variceal hemorrhage, hepatocellular cancer, ascites, encephalopathy

Outcomes and End Points Related to How a Patient with NASH Feels

Both adults and children with NASH have poorer quality of life scores compared to healthy controls [33–35]. These include total, physical, and psychological measures of symptoms and quality of life scores. Up to 50–70 % of subjects with NAFLD have been reported to have depression and/or anxiety [36]. Subjects with NASH have worse scores than those with NAFL, and, as expected, those with cirrhosis have the poorest scores compared to those with earlier stages of the disease. Those with NAFLD also have both poorer physical and mental health scores compared to US populations with or without chronic illness [34].

Given the frequency of these symptoms both in those with early-stage and advanced stage disease and their impact on the lives of affected patients, there is a need to incorporate validated tools to assess symptoms and physical and mental health in the development plans for drugs particularly in phase 2b–4 studies. This will be particularly important to establish that no unexpected “off-target” behavioral adverse event occur with a given treatment.

Outcomes and End Points Related to How a Patient Functions

Most subjects with NAFLD including NASH are able to function and maintain a job and manage day-to-day activities. There is a paucity of data regarding disability in subjects with NAFLD. In a study of subjects with varying types of chronic liver [35], obesity and NAFLD were associated with poorer physical activity compared to other chronic liver diseases and lower levels of body weight. There is a need for additional research to identify the frequency and prevalence of physical and mental disability in those with NAFLD correcting for confounders such as obesity, diabetes and its complications, etc.

Regardless of etiology, cirrhosis leads to a progressive impairment in function eventually impairing the ability to manage daily living activities [37, 38]. This negatively impacts patients and their caregivers and their ability to remain fully employed forcing many families into bankruptcy and even homelessness [37]. These data have at least two implications for drug development for NASH: in studies targeting advanced stage disease, it will be valuable to capture the functional status of individual subjects and the impact of functional impairment on caregivers and health-care resource utilization [1], and these data once again underscore the need for developing therapeutics before advanced disease develops where therapeutics may or may not fully reverse functional impairment due to the underlying liver disease [2].

Clinical Outcomes and End Points Related to How a Patient Survives

All-cause mortality has long been held as the ultimately most important outcome and thus a key end point in therapy for many chronic diseases that directly cause death. There is no question that this remains an extremely important outcome for NAFLD as well. NASH is also associated with increased all-cause mortality [9, 39, 40]. There are however numerous reasons why this is an impractical end point for clinical trials for NASH, the aggressive form of NAFLD.

Like other chronic liver diseases, NASH progresses slowly to cirrhosis, the principal driver of liver-related outcomes, over 10–20 years [39, 41]. Approximately 15–20 % of subjects progress to cirrhosis in this time frame, and once cirrhosis develops, decompensation and mortality rates are about 4 % annually, and HCC incidence increases [42, 43]. Demonstration of an improvement in mortality rates (all cause or liver related) will therefore require a large number of subjects followed over 10 years or more. The costs and logistics of such an endeavor are prohibitive and make all-cause or liver-related mortality impractical end points for drug development and approval. The only potential exception may be in studies of specific populations of subjects with NASH and established cirrhosis where these end points are more imminent. Mortality should be tracked in the context of phase 4 post-marketing studies.

There are several other key clinical end points that are particularly relevant for studies in those with NASH and advanced disease. These include the rates of hospitalization, unscheduled clinic and emergency room visits, tests performed, and overall health-care resource utilization as well as time away from work. These are particularly well suited as secondary end points which together with a primary end point that directly or indirectly measures a change in health status that impacts the clinically meaningful outcomes described above will provide a comprehensive picture of the benefits of a given intervention.

Surrogate End Points and Their Use in the Assessment of Treatment Outcomes (Table 11.2)

Table 11.2

End points related to survival

End point	Comment	Utility
Death	Strongest end point but sample size and study duration will need to be very large	Impractical
MELD score	Score of 14 identifies a point above which in the absence of transplant survival declines	Objective^a Validated
Two-point CTP	Transition from Child A to B is clearly associated with poorer survival	Objective-subjective Validated Suffer from ceiling and floor effects
HVPG	Tracks risks of complications and progression	Objective^a Validated
Composite: Ascites Variceal bleeding Encephalopathy HCC	• Strongly associated with mortality • Quantifiable • Rates of development in controls are known	Objective-subjective^a Validated
Quantitative liver function tests	Quantitative	Need more validation

^aMay serve as a primary end point for trials in subjects with NASH and advanced fibrosis

The challenges surrounding the use of “hard end points” such as mortality have made these a barrier to the development of therapeutics against NASH. It is however permissible to use surrogate end points that have been established and validated as measures of health status that are linked to alterations in the risk of the major clinical outcomes discussed above.

Surrogate end points can be broadly classified in two categories: reasonably accepted, those that are likely to predict clinical benefit [1], and generally accepted—surrogate is established to predict clinical benefit [2]. Using surrogates that the FDA accepts as a valid measure of clinical outcomes/benefit, full approval for an agent can be obtained via the “regular pathway” by pivotal trials using such surrogates as the primary end point.

Surrogate End Points for Early-Stage NASH

The long duration over which NASH evolves before patients experience outcomes creates a major challenge in the design and logistics of clinical trials for those with NASH and early-stage disease. This does not however lessen the need for the development of therapeutics for such individuals given the growing contribution of progressive NASH to the burden of chronic liver disease. It is therefore imperative to evaluate end points that can be achieved within 1–4 years and are reliable surrogates for meaningful outcomes. Moreover, these end points should reflect changes in the disease process and be biologically plausible.

End Points for Early Phase (1–2a) Trials for NASH

The principal objectives of early phase trials are to assess safety and to obtain a signal for efficacy that will guide decision making about further development for a given drug. The end points for such trials should include traditional end points for safety including data on potential hepatotoxicity. Efficacy-related end points may be those that relate to proof of mechanism or clinical efficacy. Hepatic triglyceride quantification, liver enzymes, and CK18 are biologically plausible markers of improvement and are also objective, measurable, and sensitive to change. Resolution of steatohepatitis almost never occurs without a decrease in hepatic steatosis. Serum CK18 levels, reflective of apoptotic activity, have been shown to correspond robustly with the improvement in liver histology in two phase 2b clinical trials of NASH in adults and in children, respectively, with a predictive area under the curve over 0.9.

Histology-Based End Points

The best short-term (1–2 years) end points that track the progression of NASH are currently based on liver histology. It is known that steatohepatitis, not isolated fatty liver, is associated with a substantial increase in the long-term risk of developing cirrhosis and liver-related outcomes [39, 41]. Logic dictates that reversal of steatohepatitis should therefore be related to a decrease in the risk of developing advanced fibrosis. Recently, it has been demonstrated in a clinical trial of vitamin E for NASH that those who resolved their steatohepatitis had improvement in fibrosis. Reversal of steatohepatitis is thus not only closely linked to the biology of the disease but also has been shown to reduce progression to advanced fibrosis and actually cause disease regression. It therefore meets the criteria for a reasonable short-term end point that is suitable for phase 2b or as a surrogate “likely to predict clinical outcomes” for phase 3 trials for NASH. Given that steatosis and inflammation can decrease with the development of advanced fibrosis, reversal of steatohepatitis should be accompanied by lack of progression to advanced fibrosis (stage 3 or 4) as the end point to be measured in such trials. This can also be used in routine clinical practice. The optimal duration before a liver biopsy is needed to determine histological response is uncertain. In general a biopsy may be considered after 12 months of treatment.

A decrease in the NAFLD activity score (NAS) has also been used as an end point in clinical trials. The use of this end point is limited by a lack of data describing the relationship between changes in NAS and either progression to advanced fibrosis or clinical outcomes. There is currently an urgent need to generate such data to validate the use of the NAS as a legitimate way to assess NASH and the response to therapy. The best way to generate this data is to incorporate a change in NAS as a secondary end point in randomized clinical trials.

Development of Advanced Fibrosis/Cirrhosis as an Intermediate-Term End Point

There is little controversy within academia and clinicians that the development of cirrhosis represents a significant worsening of health status and thus a clinically meaningful outcome. The development of bridging fibrosis and cirrhosis represents a histological continuum and is often considered together to represent those with advanced disease. Subjects with cirrhosis have poorer quality of life, symptom, and mental/physical health scores compared to early-stage disease [35, 37]. Cirrhosis impairs the functionality of the individual over time, and the eventual onset of complications leads to death at a well-defined rate of 4–5 % annually [40, 42, 43]. It also increases the rates of hospitalization and overall health-care resource utilization. It therefore meets all three criteria (feel, function, and survive) for a clinically meaningful outcome.

Surrogate End Points for Those with Advanced Disease

The development of an adverse liver-related clinical outcome is generally accepted to predict mortality. There are also several surrogates which are considered “likely to predict” mortality risk in subjects with cirrhosis, e.g., the Model for End-Stage Liver Disease (MELD) score , Child-Pugh-Turcotte (CPT) score , and the hepatic venous pressure gradient (HVPG) .

Liver-Related Outcome End Point

Liver-related mortality in all chronic liver diseases including NASH is closely linked to the development of hepatocellular cancer, ascites and related complications, variceal hemorrhage, hepatic encephalopathy, and eventually acute-on-chronic liver failure usually due to sepsis [40, 43]. It is now well established that the development of any one of these complications heralds an immediate deterioration in health status (i.e., clinical decompensation) and an increase in mortality risk [44, 45]. A composite liver-related outcome end point can be developed, that is, is measurable, objective, and directly related to mortality. The rates of development of these outcomes in those with compensated cirrhosis are well known [44, 45], and specific data for NASH-related cirrhosis are also known [43]. This is best suited as an end point for those with NASH and compensated cirrhosis. Even in this population, the rates of development of these outcomes will require large sample sizes or ways to enrich the population to increase the likelihood of demonstrating differences between placebo and active treatment. For individual subjects, current practice guidelines for the management of compensated cirrhosis including vaccination, endoscopy, assessment for hepatocellular cancer, and maintenance of nutritional status should be followed.

Child-Pugh-Turcotte Score

The Child-Pugh-Turcotte score was originally developed as a tool to evaluate mortality risk following portacaval shunt surgery in those with cirrhosis [46]. Over the last three decades, it has been shown to be robustly associated with intermediate-term mortality (1–5 years). Progression from Child class A to class B robustly measures worsening of a given patient’s health status and an increase in mortality risk [47]. It however suffers from a ceiling as well as floor effect of which the latter is relevant for the development of drugs for NASH. It also has a subjective element which led to its abandonment as a way to allocate organs for liver transplantation. Despite these limitations, it remains a time-tested way to assess 1–5-year mortality risk in subjects with advanced liver disease. Progression from Child class A to B or a two-point worsening of the CPT score may be considered as a failure of treatment in patients with NASH and cirrhosis receiving anti-NASH treatment.

MELD Score

The MELD score is one of the best predictors of short-term (3-month) mortality risk in those with cirrhosis. It has a greater dynamic range compared to the CPT score and is sensitive to change. All of these attributes led to its adoption to guide organ allocation for liver transplantation [48, 49]. MELD is objective, easy to measure, widely available, and backed up by a very large body of evidence as a rigorous surrogate for mortality risk.

The MELD score is not a good surrogate for outcomes in early-stage NASH, and its use should be restricted primarily to the treatment of those with NASH and advanced fibrosis (bridging fibrosis or cirrhosis). It has been shown that the benefits of liver transplant start becoming apparent once the MELD scores exceed 14 [50, 51]. Consequently, a MELD score > 14 is often considered a minimal listing threshold for liver transplantation. While it is understood that many other factors also determine if a given patient is listed for transplant, all other things being equal, a MELD of 14 or higher represents a need for liver transplant and therefore is justifiable as a surrogate end point that meets the criteria for a valid surrogate, i.e., strong relationship to mortality and outcomes, objective, easy to measure, sensitive, and widely available.

Hepatic Venous Pressure Gradient (HVPG)

The HVPG measures the difference between the wedged hepatic venous pressure and the free hepatic venous pressure. It is related to outcomes, measurable, objective, and sensitive to change. The methodology for its measurement is well established, and there is a large body of literature to support its concordance with liver-related outcomes [52, 53, 54]. Cirrhosis-related complications heralding clinical decompensation occur largely above a threshold HVPG of 10 mmHg which forms the basis for this cutoff to represent clinically significant portal hypertension [55, 56]. The proportions of subjects developing a HVPG > 10 mmHg may also serve as a surrogate primary end point in trials of therapeutics for those with NASH and advanced fibrosis assuming they have lower HVPG at entry into the trial. This end point is best suited for those with advanced fibrosis or cirrhosis. Its role in routine clinical practice remains to be determined.

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