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

 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

 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.
  National Institute of Health defines surrogate end point as “a biomarker intended to
substitute for a clinical end point”.
 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 β2 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)

Conclusion
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
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