UNIVERSITA’ DEGLI STUDI DI MILANO- UNIVERSITA’ DEGLI STUDI DI MILANO -BICOCCA BICOCCA MASTER OF SCIENCE IN MEDICAL STATISTICS MASTER OF SCIENCE IN MEDICAL STATISTICS INTERNSHIP IN NOVARTIS PHARMA INTERNSHIP IN NOVARTIS PHARMA “Statistical evaluation of a randomized Statistical evaluation of a randomized “ controlled clinical trial in phase III on controlled clinical trial in phase III on liver transplanted patients, beginning liver transplanted patients, beginning from a predetermined analysis plan”. from a predetermined analysis plan”. Supervisor: Dr Roberto Ferrara : Dr Roberto Ferrara Supervisor Student: Sofia Cividini : Sofia Cividini Student
INTRODUCTION INTRODUCTION In the last twenty years, the transplantation procedures have � become a semi-elective intervention in patients with cronic degenerative liver diseases. In particular, an always bigger number of liver transplantations � involves subjects with hepatitis C which can evolve in cirrhosis. However, it is well known the negative effect of HCV infection � on patient survival and on the duration of the graft. This negative effect mainly seems correlated to the recurrence � of the infection and maybe it is accelerated by the use of a non- selective immunosuppressive regimen such as that with the classical therapy with steroids.
INTRODUCTION INTRODUCTION Therefore, pharmaceutical research is currently engaged in the � study of alternative pharmacological therapies to use instead of the classical one with corticosteroids in order to control both graft rejection and recurrence of the infection. Recently, the use of a chimeric monoclonal antibody as � additional immunosuppressant after kidney transplantation has been approved. The target of this antibody is the α-chain of the receptor of Interleukin-2 (IL-2) in the activated linfocytes.
The Purpose of Our Study. . The Purpose of Our Study The first purpose of our study was to compare the cumulative � incidence of the graft loss and of death in patients with HCV at 12 months from the surgery. All patients were transplanted for the first time. � The patients were randomized into two groups of treatment: � 1) a group was treated with the monoclonal antibody 2) the other group was treated with the classical treatment with steroids Both groups were also treated with cyclosporine and MMF.
The Purpose of Our Study. . The Purpose of Our Study The secondary purposes of our study were the following ones: The secondary purposes of our study were the following ones: � � – we compared the incidence of the recurrence of hepatitis C at 6 we compared the incidence of the recurrence of hepatitis C at 6 and and – 12 months from the transplantation. 12 months from the transplantation. – we compared the incidence of acute rejections at 6 and 12 we compared the incidence of acute rejections at 6 and 12 – months from the transplantation. months from the transplantation. – – we compared the pure survival of graft and patient after treatm we compared the pure survival of graft and patient after treatment ent with antibody or steroids at 6 and 12 months from the transplantation. ation. with antibody or steroids at 6 and 12 months from the transplant – we compared the viral load after the treatment with antibody or – we compared the viral load after the treatment with antibody or with steroids at the baseline, at one month and at three months from from with steroids at the baseline, at one month and at three months the transplantation. the transplantation. – we evaluated the safety and the we evaluated the safety and the tollerance tollerance of the antibody versus of the antibody versus – steroids in patients with diabetes, hypercholesterolemy hypercholesterolemy, hypertension, , hypertension, steroids in patients with diabetes, coronaric disease, cataract, bone necrosis or fractures. disease, cataract, bone necrosis or fractures. coronaric
STUDY DESIGN STUDY DESIGN � This study is an open-label randomized controlled clinical trial in phase III. It involved 190 patients who were enrolled into 13 centres specialized in liver transplantation. In the following analysis we analysed only half of subjects for educational purposes. So the results that we reported here are not the real ones.
STUDY DESIGN STUDY DESIGN Patients were centrally randomized in a 1:1 ratio in order to � receive the studied drug (antibody) or the standard therapy (steroids). The inclusion criteria into the study were the following ones: � – Age between 18 and 75 years – Positivity to cirrhosis caused by HCV at the last disease stage – First liver transplantation The exclusion criteria were the following ones : � - Presence of other infections such as HBsAg or HIV - Multiple transplantation - Specific biochemical parameters alterated - Presence of cancers in the last 5 years
RESULTS RESULTS Table 7.1-1 Patients disposition overall and by treatment All enrolled patients ______________________________________________________________________________________________ All patients Antibody group Steroids group n (%) n (%) n (%) ______________________________________________________________________________________________ Enrolled 101 Randomized and treated 101 50 51 Completed the study 79 ( 78.2%) 39 ( 78.0%) 40 ( 78.4%) Discontinued 22 ( 21.8%) 11 ( 22.0%) 11 ( 21.6%) ______________________________________________________________________________________________ Main reason for discontinuation Death 11 ( 10.9%) 5 ( 10.0%) 6 ( 11.8%) Adverse event(s) 5 ( 5.0%) 3 ( 6.0%) 2 ( 3.9%) Abnormal lab/test results 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) Lack of efficacy (graft loss) 5 ( 5.0%) 3 ( 6.0%) 2 ( 3.9%) Protocol violation(s) 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) Withdrawal of consent 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) Lost to follow-up 1 ( 1.0%) 0 ( 0.0%) 1 ( 2.0%) Administrative reasons 0 ( 0.0%) 0 ( 0.0%) 0 ( 0.0%) ______________________________________________________________________________________________
RESULTS RESULTS Table 7.2-1 Protocol violations and deviations Safety population Antibody group Steroids group N = 50 N = 51 n (%) n (%) ________________________________________________________________________________________________________________ Patients with any protocol violation or deviation 11 ( 18.0%) 14 ( 21.5%) Patients with any major protocol violation or deviation 2 ( 3.3%) 3 ( 4.6%) Patients with any minor protocol violation or deviation 9 ( 14.8%) 11 ( 16.9%) ________________________________________________________________________________________________________________ Major protocol violations or deviations 1 - HCV-negative patients 0 ( 0.0%) 0 ( 0.0%) 2 – HBsAg- or HIV- positive patients 0 ( 0.0%) 1 ( 1.5%) 3 - no treatment with MMF and CsA after transplantation 2 ( 3.3%) 2 ( 3.1%) 4 – multiple organ transplant or previous liver transplant 0 ( 0.0%) 0 ( 0.0%) ________________________________________________________________________________________________________________ Minor protocol violations or deviations 5 - use of background immunosuppressants other than MMF and CsA 5 ( 8.2%) 7 ( 10.8%) 6 - age less than 18 or greater then 75 years 0 ( 0.0%) 0 ( 0.0%) 7 - anemia (hemoglobin < 6 g/dl) 4 ( 6.6%) 4 ( 6.2%) 8 - creatinine > 18 mg/dl or renal dialysis before transplantation 0 ( 0.0%) 0 ( 0.0%) 9 - neoplasia in the last 5 years † 0 ( 0.0%) 0 ( 0.0%) 10 - severe active infections except cholangitis, previous myocardial infarction or other severe and unstable medical condition 0 ( 0.0%) 0 ( 0.0%) ________________________________________________________________________________________________________________ † except basocellular or squamocellular skin tumors successfully excised
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