American Association for the Study of Liver Diseases Endpoints Conference: Design and Endpoints for Clinical Trials in Primary Biliary Cirrhosis (2010)

A group of multidisciplinary experts on primary biliary cirrhosis (PBC) and its complications convened on May 31, 2009, under the aegis of the American Association for the Study of Liver Diseases (AASLD) in order to identify the most appropriate design and endpoints for clinical trials of PBC based on current evidence and expert experience. The natural history of PBC was reviewed as well as current therapies. The current approaches to evaluating therapies for disease progression and symptoms as priorities were discussed. Appropriate aspects of trial design including entry criteria, study duration, and appropriate handling of issues such as stratification of subjects and use of ursodeoxycholic acid (UDCA), were identified and discussed. After a full day of presentations, in a consensus manner, appropriate endpoints for clinical efficacy trials regarding PBC and its complications were agreed upon and are reported in this summary. AASLD, American Association for the Study of Liver Diseases; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AMA, anti-mitochondrial antibodies; AST, aspartate aminotransferase; ELISA, enzyme-linked immune assay; EV, esophageal varices; FIS, fatigue impact score; FDA, U.S. Food and Drug Administration; HCV, hepatitis C virus; MRS, Mayo Risk Score; MELD, Model for End-Stage Liver Disease; PHG, portohepatic vein gradient; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid; ULN, upper limits of normal; VAS, visual analog scale. PBC is a relatively rare but important cause of chronic cholestatic liver disease that affects predominantly middle-aged women.1 Elevations in serum alkaline phosphatase (ALP) levels are the biochemical hallmark of PBC. In this context, the best diagnostic tool for PBC is the measurement of anti-mitochondrial antibodies (AMA), which are characteristic of PBC and are present in at least 95% of the cases.2 Liver biopsy is not required for clinical diagnosis in PBC,3 but may be helpful in selected situations such as stratification of patients within clinical trials and in some cases may be used as study endpoints. Earlier epidemiological studies report an annual incidence ranging from 2.27 to 32 per million4, 5 with a female-to-male sex ratio averaging approximately 10:1,6 although over the last decade the disease is reported more frequently, perhaps at least in part due to greater disease awareness.7 PBC occurs in all races and ethnicities, the highest rates of prevalence and incidence have been within Caucasian populations from the United Kingdom,4 Scandinavia,8 and Minnesota,9 and it is infrequently reported in Africa and the Indian subcontinent. PBC is a slowly progressive disease that causes substantial loss of intrahepatic bile ducts, ultimately resulting in cholestasis, advanced fibrosis, cirrhosis, and liver failure. As such, PBC is an important indication for liver transplantation.1 Cirrhosis may also lead to hepatocellular carcinoma in PBC. Histologically, the disease is characterized by chronic portal inflammation with infiltration, destruction and loss of the epithelial cells in the small-sized and medium-sized bile ducts.10 Progression of disease occurs at different rates and with varying degrees of severity in different patients.2 The natural history of PBC can be divided into four phases. The silent or preclinical phase is characterized by isolated AMA positivity and normal serum biochemistries11; this phase may last many years. The next phase is characterized by gradual elevation of the serum ALP levels. The vast majority of newly diagnosed patients with PBC presents without symptoms attributable to liver disease and are in this asymptomatic phase. Although this phase may last up to 20 years, only 30%-50% of patients remain asymptomatic after 5 years of follow-up.12 As PBC is diagnosed increasingly earlier, this percentage may be increasing. Patients in the symptomatic phase will most often complain of fatigue and/or pruritus, but may also report abdominal pain. Symptoms related to portal hypertension usually appear later, with 20% developing ascites and 10% developing bleeding varices within a 10-year period.13 Most patients who develop portal hypertension are often either anicteric or mildly jaundiced. If untreated, median survival ranges from 6 to 10 years, with an accelerated course after development of ascites and hepatic encephalopathy. Once progressive jaundice develops, patients enter a pre-terminal phase, which can last up to 2 years.13 UDCA has been the drug most widely evaluated in the treatment of PBC. Treatment with UDCA may delay disease progression and prolong survival free of liver transplantation.14 Most of the trials of UDCA have not recruited sufficient patients to have the power to show an effect of therapy on survival. Therefore, the evidence that UDCA inhibits the progression of the disease has been delayed until long after the completion of the trials that demonstrated improvement in markers of cholestasis. Several studies evaluating long-term survival of patients have been published and uniformly they indicate that those who demonstrated biochemical response to adequate doses of UDCA for prolonged periods of time have longer survival free of liver transplantation and longer overall survival.15-18 Currently, treatment with UDCA in a dose of 13-15 mg/kg/day is recommended as therapy for PBC by the AASLD19 and is approved for this indication by the U.S. Food and Drug Administration (FDA). Despite significant evidence that points to an autoimmune etiology of the disease, the precise etiology of PBC remains unknown. As long as the etiology of PBC remains unidentified and not measurable, determining surrogate endpoints is particularly difficult. A parallel can be drawn to the history of conducting clinical trials in hepatitis C. With the identification of the hepatitis C virus (HCV) and the development of internationalized units of amplified HCV RNA, it became possible to use HCV RNA as a surrogate endpoint in clinical trials. Histological improvement in fibrosis, decline in the rates of death/transplantation, and other “hard outcomes” were not demonstrated until years after sustained virological response. Importantly, these hard outcomes were not realized before licensing and widespread availability of antiviral medication. The cost of large randomized placebo controlled trials of HCV was significant and was borne largely by the pharmaceutical industry. If the endpoints of HCV trials had rested upon hard outcomes such as survival, the duration and cost would have likely prohibited the development of what we now know to be successful therapies. Similarly, without a known etiology of PBC, the design and execution of clinical trials is significantly hampered. Multiple issues add to the challenge for design and execution of clinical trials in PBC. The relative rarity of PBC, as compared to HCV, poses a challenge to achieving requisite sample sizes. In addition to small sample size, the slow rate of disease progression limits the evaluation of effects of therapy on survival and survival free of liver transplantation. Other issues that make trials even more complex to evaluate include the wide range of disease severity and response to UDCA, which are often inversely correlated. Meta-analyses could help overcome the effects of limited sample size; however, the marked heterogeneity of some of the clinical trials conducted to date has limited the interpretation of combined analyses. Thus, standardization of study design and appropriate endpoints are crucial for the advancement of clinical research in PBC and for capturing benefits in health outcomes that might be achieved with new interventions. A detailed description of the diagnosis of PBC in clinical practice is beyond the scope of this report. The interested reader is referred to the recent AASLD practice guidelines published on PBC.19 For the purpose of enrollment into clinical trials, the presence of AMA in the context of cholestatic liver biochemistries (i.e., elevated alkaline phosphatase, with or without mild elevation of aminotransferases) in the absence of biliary obstruction19 should be considered standard entry criteria. This is because little is known about AMA-negative PBC and whether it represents a different pathological entity. Furthermore, AMA-negative patients represent such a small percentage of patients with PBC that their exclusion from clinical trials is justified. There are several methodologies for determining AMA, including indirect immunofluorescence and enzyme-linked immunosorbent assay (ELISA). ELISA is recognized as more sensitive, but perhaps not as specific.20 Not all centers provide both options for testing; therefore, no specific type of AMA testing should be required for trial entry criteria. Detection of AMA by any method is acceptable for diagnosis. The presence of antibody, rather than the magnitude of antibody level, establishes AMA-positivity. Liver biopsy is also considered desirable before entry into most trials aimed at altering the course of the disease. Diagnosis of concurrent pathological processes is an invaluable consideration for liver biopsy; steatohepatitis has been documented in up to 5% of other forms of chronic liver disease,21 and the presence of “overlap” features of autoimmune hepatitis are best documented by liver biopsy findings. In a recent study, 19% of otherwise typical PBC could be given a diagnosis of “probable” autoimmune hepatitis, according to the revised Autoimmune and were considered as hepatitis The of hepatitis in biopsy was of features that and After 6 years of the patients with had significantly clinical outcomes than the PBC the of liver biopsy to the was recognized that in study, the presence of AMA and cholestatic in a had a for the presence of PBC,3 the for a liver biopsy for diagnostic this study was conducted and in centers of for PBC by is not whether these would the widely patients liver have hepatitis may have a more progressive disease than patients without this hepatitis is an important Other may also have such as the of Therefore, treatment trials for the liver disease of PBC for Liver may also be a desirable study endpoint progression or For some trials, such as those evaluating symptoms such as and fatigue in patients with an diagnosis of PBC, liver biopsy for stratification or as a study endpoint may not be as Thus, a liver biopsy at study entry may not be The diagnosis of PBC for enrollment of patients into clinical trials should be by the presence of in the absence of biliary and the presence of AMA of or diagnostic Liver biopsy before entry into trials is desirable for stratification and may have a as a endpoint in longer trials. evaluating treatment for and fatigue in patients with an diagnosis of PBC may not a liver biopsy at study There is an the duration of the study and the of study be long and the of in large to that the normal The consensus was that for biochemical a of is in ALP levels should be greater than which is within natural disease. For a study of at least 2 years is based on studies that have the natural history of For symptoms such as fatigue and pruritus, a study duration of approximately may be The duration of trials should be based on the primary endpoint a of are a of 2 years are severity as fatigue and approximately may be As in other trials in patients with PBC may be to disease heterogeneity and would include that may the endpoints of the study and the Although is to large stratification will make that an important is the study is in PBC trials, which to be limited in size, it may be important in large trials is more likely to in even the study history studies have identified markers of progressive disease in PBC, including but not limited response to of hepatitis and features of with autoimmune biochemical markers and presence and/or of portal specific and serum markers of have been to survival in PBC. several well the Mayo is the most widely at least in the United and the and of and response to For the has been used as a to the benefits of including therapy and liver The would be a to patients for survival of studies as well as clinical trials. it has been used in practice to patients and help make clinical This has the of the survival in patients with survival. all the serum markers to serum is the best of several of the more features upon which to which are important to use for stratification of subjects in a clinical trial on the endpoint For in a trial evaluating a long such as survival, stratification for disease (i.e., of may be may also be by their biochemical may be used to that patients with advanced PBC are to only a limited of trials have stratification into in their trial in trials should be UDCA is widely considered the standard of for PBC in and or UDCA treatment is considered and Therefore, new trials will likely have to UDCA with or without the new After a of of UDCA subjects can be divided into and biochemical Therefore, patients should be on adequate doses of UDCA and it is important to after UDCA before testing any new drug in order to improvement in biochemical is known that improvement in ALP levels may up to 5 a delay is considered a response to UDCA at is a of long-term patients with PBC who have achieved a biochemical response to UDCA have been to as long as the normal response has been be by in the Mayo 2 the upper limits of normal the ULN, aspartate 2 ULN, and the in ALP of more than of or to a normal or the of and/or after treatment or both were at The were recognized as the best and to and recommended for use in trials. treatment would be best by biochemical Once efficacy is treatment with the new drug could be compared to UDCA in was recognized that this might the of testing new therapies only in subjects who might be advanced to to any it is to patients from a treatment that likely their survival the effect of the new drug is unknown. The of primary that to those who are AMA without liver disease (i.e., with normal liver is and be at this trials with a new should patients with biochemical response after of treatment with an adequate dose of biochemical response should be as ALP ULN, 2 ULN, and trials should UDCA with or without the new efficacy is treatment with the new drug should be compared to of patients who are without liver disease is not There are endpoints for clinical trials in PBC. The hard endpoints of or liver desirable of were recognized as likely in a disease progression and the limited availability of study are the these endpoints are not to therapy could be as improvement or of progression in biochemical portal or liver to therapy could also be as improvement or of progression in symptoms such as fatigue or were considered to be important of and study the of the disease which is most to the therapy markers are to in large trials and are markers of disease and has been demonstrated to be the most important serum of and is a desirable The of as an endpoint is that it only in of the disease and is not a is in improvement in patients with mild to disease, a group which may be the most to of ALP to therapy has been to be a of both and liver in PBC and is used in clinical practice to the progression of the it is an acceptable to PBC of UDCA trials demonstrated that of ALP, a large was with survival than The of or liver transplantation as primary is The of biochemical markers is a primary endpoint for the desirable biochemical response should be ALP ULN, 2 ULN, and studies clinical such as and/or and the for liver are both and to the use of as endpoints can be Risk such as the Mayo Risk and the Model for End-Stage Liver survival. these are most in patients with sufficient hepatic to have these a of patients in the The was and as an of survival in patients with PBC, although at a time patients to present with more liver disease. trials of UDCA have used the to survival with therapy compared to survival. from the as serum it is to in disease. should not be used as primary as they are to in mild and disease. Mayo could be as a endpoint in clinical trials. hypertension and its complications develop in patients who are not with In an study, approximately of patients with PBC were to develop esophageal varices over 6 and rates as as within 2 years have been This may be significantly after by UDCA but are Although some trials in PBC have complications related to portal hypertension as a the majority of the clinical trials in PBC conducted to date have In the trials that have the development of has been the most endpoint of A studies have that the development of in patients with PBC to the development of symptomatic disease and also of other complications related to portal hypertension such as ascites or encephalopathy. portal hypertension can be present in the absence of varices and can only be by measurement of the portohepatic A recent study including of the portohepatic in patients with PBC reported the presence of portal hypertension 6 in of and portal hypertension for the of bleeding from in 20% of In this study, significant in survival were patients at as 6 and at was with survival. Furthermore, improvement of in response to UDCA was with survival free of liver transplantation. the development of portal hypertension is as an endpoint for trials is justified. hypertension can be by several different by the development of development of development of or by or portal are acceptable but the best to portal hypertension in a trial the relative and cost for within the of the evaluation is the standard for the development of but it is and not portal hypertension which may be present in the absence of is but is not recommended for of based on such as may be in specific clinical but not provide the to be used as in clinical trials. measurement is and to small in portal it is and not such as may be in the of portal hypertension in patients with but study and hypertension can be by several different including development of development of development of or by or portal hypertension can be a primary endpoint in treatment trials of portal hypertension as endpoints is that may be Histological evaluation within the context of clinical trials should on the that the disease or that are of that have been identified as of survival fibrosis, bile of cirrhosis and In the study, limited to the portal was as a history studies have progressive disease within years, with progression of in of patients without cirrhosis at over a median of years, of patients with cirrhosis, only of may help study as well as treatment and trials of therapy for PBC that have of hepatitis have the of that this is to The study this into a with to elevated and Thus, of hepatitis would appear to be in clinical trials. This however, at only and these may be to A of for portal vein and features of is use of beyond the use of and and may to be considered and for by in liver is a desirable for clinical trials of PBC. current including the used and not provide for many features that have been with is of that several recognized of PBC that may to portal hypertension and/or progressive are not part of any of these including portal inflammation and and to of The of fibrosis, for HCV and not PBC, provide a of and has been in only PBC to the development of hard it also of inflammation and which are also considered and are likely more to over a time The of and a new for PBC to these is by of the the of this study of liver in PBC are not The recognized of liver biopsy for PBC are A include the absence of diagnostic on any given biopsy due largely to the heterogeneity of disease the The and may be because biliary is characterized by with of the hepatic and may be clinical evidence of portal hypertension without evidence of advanced on the the presence of is recognized in Histological progression not at the rate as clinical and the presence of cirrhosis at diagnosis not with the presence of has been used by several to that most treatment patients with PBC will within 2 years. Similarly, used a and that only and of patients remain in after and years, Although improvement in liver is a desirable endpoint for clinical trials, current are therefore, the use of as a primary endpoint is evaluation of features in liver treatment remains as a markers of fibrosis, such as serum and have that are For in a long-term study of patients with PBC, serum markers of liver into the Liver the development of complications or particularly at in the disease and 6 years to the the of other such as and is to the use of surrogate markers of include cost and/or limited Furthermore, they are considered to use as isolated primary endpoints of a clinical The use of these as endpoints is that may be endpoints should not be used as primary endpoints in treatment trials. The use of these as endpoints is that may be The of PBC is of a relatively chronic liver disease, ultimately to advanced liver disease with its The use of UDCA may lead to successful disease in some As such, symptoms which are of the development of advanced disease, such as fatigue and pruritus, have a clinical Therefore, improvement in of including fatigue and pruritus, is an increasingly important for studies in patients with PBC. is a consensus in the that fatigue to of patients in most disease it can be a to as this is a relatively to fatigue into the and fatigue The is a which patients to rate the impact of fatigue on aspects of over the The impact on is into levels of severity which are from to four greater to a of The of the impact of fatigue on and and for this has been in studies of patients with The is of and for use in The of to and and and has been used in other studies to fatigue severity and response to The of these to in the context of remains in PBC. is best by or a visual analog in long-term The is a tool that the duration, and of Although it has been to in PBC, it is new and has been widely The VAS, its and in and has been widely used in the therefore, is a and For with a is considered because of its and in is important that subjects any of these at the time of the as both fatigue and have a and are in the trials, it is important to that fatigue the course of the and may with disease should be by or the fatigue of should be by or The to identify the cause of the disease can have a impact on the of endpoints for clinical trials. As an for hepatitis studies in the the endpoint was now the endpoint is of the a in which is a known etiology not in PBC. There are a of of to identify including the of the immune as well as or other but these are not that are at the presence of such as have to some but is not a and this may not be possible until a cause is the cause of PBC be the of endpoints for clinical trials may be group of that have been used are those at the immune response. and have not demonstrated Other therapies or are such as therapies are at of including the with some evidence of is and studies are with for patients with PBC. The that in the are with may lead to at this is a of the of the disease, and is an on altering with is on the that would that any of these therapies will have an impact on trial design in the is that new of new of or a will be identified to help in the design of PBC affects than in the United and has been by the as an disease. If new trials are patients who are biochemical to UDCA, the of study subjects to than Thus, it is that clinical trials will the of a large of A of centers upon the study of PBC, including in biliary and liver transplantation is to and clinical trials of Other important issues such as the and of PBC and could be in all autoimmune liver including hepatocellular and biliary autoimmune were within the The expert with the in the of of and of of United for Drug and Food and Drug