Clinical endpoints in organ transplantation

The aim of most of the clinical trial is to estimate the endpoint and that serves as the goal of the clinical trial. e.g. response rate and survival. An endpoint in a clinical trial is a consequence which is measured. A clinical end point gives us a measure of how a patient feels, functions or how long a patient lives. Surrogate end point is quantitative factor used as a replacement for end point. Intermediate end point is a factor that is in between the pathway between an intervention and end point. It could be binary like graft rejection Vs graft survival, continuous e.g. serum creatinine (Hariharan et al, 2003). Sometimes to measure the endpoint a biomarker can also be used. It is an indicator of response produced for an intervention. End points are important in clinical trials as the have the capability to predict the outcome of the patients in the study using biomarkers or using other factors (Hariharan et al, 2003). They are safe, cost-effective and accurate as outcome could be established well before the end. Clinical trial endpoints Disease free survival For any drug, if it could improve survival rate of patients then the chances of its approval increases significantly and this is a gold standard for any drug to get approved. Survival is undisputed end point as no bias is possible from the side of investigator. The Disease Free Survival is used to assess the outcome of a treatment or an intervention which can lead to freedom from disease such as surgery or surgery plus adjuvant therapy (Lachenbruch et al., 2004). During the period of disease free survival disease may reoccur due to some factors but would not lead to death. The reoccurrence of the disease could end their term of disease free survival but they will not die. Like some patients in survival cures will not die similarly in disease free survival curves only a few patients will undergo relapse of the disease and then plateau phase is attained indicating the patients in which disease did not reoccurred. Patients in which disease reoccurred will survive for some time and will not die as soon as disease reappeared (Lachenbruch et al., 2004). Progression free survival Recently time to progression (TTP) has been accepted as satisfactory end point in clinical trials. Using TPP end points in trial can be obtained in short duration, second-line therapies do not cause confounding in TPP (Lachenbruch et al., 2004). But TPP had to be done with great accuracy than other trial end points. TPP gives an estimate value and can show variation as they depend on when disease progresses and usually progression of disease is not measured and number of patients. The Progression Free Survival is used to assess the outcomes of an

intervention or treatment for a disease which has already progressed and not is not in initial phase. Usually in progression free survival, disease becomes worse and progresses (Lachenbruch et al., 2004). To get the correct outcome from the trial precise evaluation of TPP is important to evaluate each factor at baseline and during follow up evaluation should be done using same tools and technology and this makes use of TPP in clinical trial very costly. Response duration The response duration is often used in assessing the consequences for an already progressed disease (Lachenbruch et al., 2004). Usually disease reappears or relapses during the progression of the disease. So in trials were such kinds of end points are to be studied a subgroup of patient population is selected as only those patients are required for the trail who will respond and duration of response time is measured (Hariharan et al, 2003). Quality of life assessment Evaluation of patient s quality of life is a significantly important end point in a clinical trial as it shows patient s views about the clinical benefit (Lachenbruch et al., 2004). QOL are not used much as defining the variables of QOL is complex and tedious task. Quality of life can arise questions that sometimes unrelated to the study and can have impact on the result. QOL exhibits the evaluation of symptoms of disease, toxicity and effect of the treatment and well being on worldwide basis (Roep and Peakman,2010). QOL is very difficult end points in a trial as these depends on reporting by the patients which is not always correct and it is difficult to verify the reports of each patient and to follow them over time. In order to get good results from such trials bias should be reduced by double blinding them or by using a placebo group (Lachenbruch et al., 2004). They protocols, instruments and tools used should be checked. Usually QOL studies are proposition directed studies but missing data and involvement of many end points can make the study complex and also there is a possibility that by itself improvement would have taken place (Roep and Peakman,2010). For accurate prediction of endpoint two factors are important- predictive and surrogate. Clinical/ primary endpoints Good clinical endpoint must be clinically connected and related to the clinical event of the patient which he or she may avoid. A clinical event should be sensitive. Often consequence which is measured and is clinically important is quality of life. Predictive variable or primary end point takes into consideration the variation in endpoint e.g. kidney allograft rejection could be predicted by creatinine levels in serum or by examining the

immune system activation (elevated levels of mRNA) (Hariharan et al, 2003). These variables or factors alone are not an effective way of predicting the endpoint instead if multiple variable are taken into account the level of accuracy in prediction of outcome could be greatly enhanced. Problems with clinical endpoints y y y It is difficult to do trials in which primary endpoint is death which is not desired from a trial. When the events occurring in a trial are so small, that no statistical significance could be drawn from them. Urgency is assessment of interventions which could offer radical cure can affect the total outcome.

All the above factors make evaluation of primary clinical endpoint difficult and arises need for other endpoints which can act as substitute for primary end point. Surrogate end points In trials surrogate endpoints are finding increased use and have replaced true endpoints for studying disease free survival but the role of surrogate end point in a trial is disputed as their reliability is questionable. In order to study, eradication of disease and disease free or just survival can take long duration and high associated cost is very high. So in order to reduce duration of the trial surrogate end points are used and time and cost are correlated so reducing time would affect cost as well. Unlike in long term studies surrogate end point do not following of patients for long time and this reduces chances of missing values and data as patients may skip follow up or sometimes patients are lost as they move to some other places (Roep and Peakman,2010). Use of surrogate endpoint in a trial first requires identification of surrogate markers which could be measurable and are related to biology of the disease. Problems arises in the use of surrogate endpoints as surrogate markers are not easy to identify and their use is successful only if surrogates have high degree of relation with clinical endpoint of the disease (Roep and Peakman,2010). Examples of surrogate endpoints are blood pressure effects or prostate-specific antigen levels. Properties of surrogate end points y It is used to evaluate the effect of an intervention or treatment which can be related to clinical end point but their relationship is not sure.

y National Institute of Health defines surrogate end point as a biomarker intended to substitute for a clinical end point . y They are also known as replacement or substitute end points. End point are usually measured in phase II trials and in phase III trials In phase II trial when an intervention is introduced to improve the medical condition for a treatment. In phase III trials often clinical end points are measured. Trials where death or organ rejections are the clinical end points those trials are difficult to conduct and are time consuming and long duration. In those studies surrogate end points can be used to reduce the cost and duration of the study. Since surrogate endpoints are predictive in nature they can be measured early in the study can fasten the approval process only problem with surrogates are they are not reliable. Composite endpoints Composite endpoints are used to study those diseases which are rarely found in a normal trial or for such disease which occur in population but to find such disease in a trial, it requires a large number of subjects and long duration. So when such are disease have to be studied which requires a long time and large patient population, and then the study become difficult as it will be very expensive and lengthy trial (Roep and Peakman,2010). In such studies instead of measuring a single endpoint a combination of endpoint are measured. But the elements of the composite endpoints should correlate to the pathphysiology of the disease and to the extent of severity. Often the results of composite end points could be so complex to interpret and reach any conclusion (Roep and Peakman, 2010). End points in renal transplant Endpoints in renal transplantation are of 2 types conventional and clinical endpoints Conventional endpoints Short term graft survival- trials for immunosuppressive drugs in renal transplantation was done for which end points was 1 year survival of the graft (refer table 1). In a European study, patients who received cadaveric kidney were studied using cyclosporine A and azathioprine & prednisone and were followed over time to assess the outcome (Hariharan et al, 2003). It was found that the graft survival rates were higher in patients on cyclosporine A therapy than with patients on azathioprone & prednisone therapy (Hariharan et al, 2003). Hence short term survival of graft was found using cyclosporine A.

Acute rejection- Improvement in 1 year survival rates was observed in patients on cyclosporine therapy but usually transplantation trials are done using acute rejection as the end points. Acute rejection affects the graft rejection and it serves as an endpoint in immunosuppression (Hariharan et al, 2003). Long term survival - it is recommended that long-term survival be used in clinical trials as end point. Although the short term end points are cost effective, predictive and duration of study is also short but they are not accurate and diversity in patient population (Hariharan et al, 2003). Although long time survival rates are clearly a good end points but the time duration make them unsuitable to be used as standard and still quest for short term endpoints is on which could satisfy requirement of long term survival (Hariharan et al, 2003). Short term end points predicting long term survival- it is important to recognize the marker with in short time after the transplantation has been carried out (Hariharan et al, 2003). As these, markers can be used to make estimation of the survival of the graft for long term (Hariharan et al, 2003). This method is very valuable as it is quick and cost effective and is boon for patients which could possibly show poor survival of graft in future. Short term end points could be differentiated into clinical, histological and immunological end points (Hariharan et al, 2003). Clinical endpoints Serum creatinine- after the transplantation, it is important to perform renal function at the time of discharge of patient or after few days after the transplantation as it serves as a marker for proper functioning of kidney. Serum creatinine levels (renal function test) are increasingly being related to long term survival of the graft. Renal function is an important marker and using serum creatinine levels patients who are likely to have acute graft rejection can be identified(Hariharan et al, 2003). Usually pharma companies in order to prove the efficacy of the drug performs short-term renal function studies and uses renal function as end point. Creatinine clearance Some times in clinical studies creatinine clearance is used instead of measuring serum creatinine levels as clearance measurement is more accurate and could be easily be used as an endpoint (Hariharan et al, 2003). To measure clearance either nuclear studies are done or urine is collected at 24- hour intervals and analyzed. In a study conducted recently, clearance was calculated at 6-months and 1 year and it was shown that creatinine clearance and long term graft survival are related but it is more easy and feasible to use serum creatinine as marker due to its simplicity (Hariharan et al, 2003). Cystatin C- it also assesses renal function and is marker of renal function. In several clinical trials cystatin c has been compared with serum creatinine and creatinine clearance in patients

undergone renal transplant (Hariharan et al, 2003). It has been shown in trials that cystatin c is related to serum creatinine and creatinine clearance and has accuracy better than that of serum creatinine but has equal or lower accuracy when compared with 2 microglobulin and creatinine clearance. As already mentioned that cystatin c has advantage over serum creatinine but has several drawbacks which limits it use in trials- it is very costly and accuracy could be affected by free availability(Hariharan et al, 2003). Renal histology Since ancient times histological studies of kidneys are done to assess the kidney dysfunction and could be used as end point. Histological acute rejection- till recent times histological observations were the only way to assess the working of transplant and for only those patients in which kidney was not functioning properly(Hariharan et al, 2003). Biopsies were performed to assess the performance of kidney in stable patients and to assess subclinical acute rejection which do not affect the graft and had led to better preservation of renal function. Biopsies here serve as an endpoint (Hariharan et al, 2003). Chronic allograft nephropathy- late graft failure causes chronic allograft nephropathy (CAN) and till now no clinical trial has assessed chronic allograft nephropathy. Assessing chronic allograft nephropathy require a huge patient population and long follow up duration which makes assessing these end point in a trial expensive. So more emphasis is given to chronic histological changes, as they are easy to evaluate. Indexes such as Banff Score Index and the Chronic Allograft Disease Index (CADI) score are being used for renal scarring and have been related to failure of graft. Anti donor antibodies ± Human leucocyte antigen (HLA) typing is very important part of transplantation and transplantation is done after some degree of match in terms of HLA exists between recipient and donor. HLA can have severe affects on short and long term graft survival (Hariharan et al, 2003). Mismatched HLA can produce anti-donor antibodies against the received organ soon after the transplantation is done. Generation of anti-donor antibodies is related to the immune system injury and in extreme conditions transplantation failure (Hariharan et al, 2003).

Table 1. showing various end points and there advantages adapted from (Hariharan et al, 2003)

Table 2 showing endpoints in renal transplantation adapted from (Hariharan et al, 2003)


To conclude we can say that graft survival rates have improved and rejection rates have gone down and these are demanding new endpoints to effectively assess the outcomes of the

transplantation. Short term markers are developing gradually and should be included in future studies as they can predict the outcomes quicker. Markers like serum creatinine levels, creatinine clearance and cystatin c have been shown to relate to long term studies effectively and hence should be applied in trials as well as in practice. Other markers like histological studies, immunological markers are more providing more accurate way to assess the results of a trial. Since these endpoint are newer so have not been applied independently till now but they could be applied along with clinical and conventional end points as composite endpoints and could serve as good indicator of , rejection, graft loss and death Reference: Hariharan, S et al. (2003). Evolution of Endpoints for Renal Transplant Outcome American Journal of Transplantation. Vol 3: 933 941 Hernández, D. (2007).Surrogate end points for graft failure and mortality in kidney transplantation. Transplantation Reviews. 21 97 106 Lachenbruch, P.A. et al. (2004).Biomarkers and Surrogate Endpoints in Renal Transplantation: Present Status and Considerations for Clinical Trial Design. American Journal of Transplantation; 4: 451 457 Roep, B.O and Peakman, M.(2010).Surrogate end points in the design. Nature review. Vol 10 Washburn, K. (2008). Endpoints in trials for clinical liver transplantation. Current Opinion in Organ Transplantation. 13:252 256

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