Appropriate Endpoints for Renal Transplantation Clinical Trials
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Drug Infurmution Juurnal, Vol. 31, pp. 207-212, 1997 Printed in the USA. All rights reserved.
APPROPRIATE ENDPOINTS FOR RENAL TRANSPLANTATION CLINICAL TRIALS CLAUDIO PONTICELLI, MD, FRCP Director
MARIAROSARIA CAMPISE, MD Assistant Division of Nephrology and Dialysis, IRCCS Ospedale Maggiore, Milan, Italy
The patient and graft survival are the primary endpoints to evaluate safety and eflcacy of the immunosuppressive treatments in renal transplantation. Today, however; the results ure so good that a huge number of patients is needed to find statistically significant differencesbetween treatments. Secondary endpoints are, therefore, used. Infections and other side effects are good endpoints for safety. Acute rejection is the best surrogate endpoint for eflcacy. The diagnosis of acute rejection rests on an increase of plasma creatinine but how much the increase should be to define rejection is still uncleai: Moreover; a number of noninvasive techniques can be used to exclude causes of graft dysfunction other than rejection. Thus, renal biopsy may be required to confirm the diagnosis. The severity of acute rejection may be used as a tertiary endpoint, but the criteria for assessing the severity of rejection still need to be standardized either based on clinical or histological variables. Key Words: Surrogate endpoints; Transplantation;Efficacy; Safety; Rejection; Endpoint
INTRODUCTION
THE MAIN AIM OF controlled therapeutic trials in renal transplantation is to compare the safety and the effectiveness of different immunosuppressive regimens. The primary endpoint to assess effectiveness is certainly represented by the graft survival which strictly depends on the ability of an immunosuppressive regimen of preventing rejection. On the other hand, patient survival probably represents the most appropriate endpoint for assessing the safety of immunosuppressive therapy. In fact, while for other vital organ
Presented at the DIA 31st Annual Meeting, June 25-29, 1995, Orlando, Florida. Reprint address: Dr. Claudio Ponticelli, Divisione di Nefrologia e Dialisi IRCCS Ospedale Maggiore, Via Commenda, 15, 20122 Milano, Italy.
transplants patient survival is strongly related to the capacity for preventing irreversible rejection, in the case of renal transplantation whenever the allografted kidney fails, because of rejection or other causes, the patient can be maintained in life with dialysis. Thus, in these patients, mortality is caused by the complications of immunosuppressive therapy, mainly infections and cardiovascular diseases, rather than by rejection. Since most of the events in renal transplantation occur within the first months, the one-year patient and graft survivals are usually considered. After the introduction of cyclosporine, however, the results with renal transplantation are so good that many groups report a one-year graft survival ranging between 80% and 90% and, obviously, an even better patient survival (1,2). This means that to determine differences of less than 5% between
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