Statistical evaluation of a randomized Statistical evaluation of a - - PowerPoint PPT Presentation

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 Supervisor: Dr Roberto Ferrara : Dr Roberto Ferrara Student Student: Sofia Cividini : Sofia Cividini

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
• n patient survival and on the duration of the graft.
• This negative effect mainly seems correlated to the recurrence
• f 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

• f 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 transplant with antibody or steroids at 6 and 12 months from the transplantation. ation. – – 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 with steroids at the baseline, at one month and at three months from from the transplantation. the transplantation. – – we evaluated the safety and the we evaluated the safety and the tollerance tollerance of the antibody versus

• f the antibody versus

steroids in patients with diabetes, steroids in patients with diabetes, hypercholesterolemy hypercholesterolemy, hypertension, , hypertension, coronaric coronaric disease, cataract, bone necrosis or fractures. disease, cataract, bone necrosis or fractures.

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

RESULTS RESULTS

Table 7.3 Table 7.3-

• 1

1 Number of patients in the analysis populations overall and by t Number of patients in the analysis populations overall and by treatment reatment All randomized patients All randomized patients _______________________________________________________ ______________________________________________________________________________________________ _______________________________________ All patients Antibody group Stero All patients Antibody group Steroids group ids group _______________________________________________________ ______________________________________________________________________________________________ _______________________________________ n n n n n n _______________________________________________________ ______________________________________________________________________________________________ _______________________________________ Randomized and treated Randomized and treated (ITT and safety (ITT and safety evaluable evaluable pts pts -

• SAF)

SAF) 101 50 101 50 51 51 ITT patients alive with functioning graft ITT patients alive with functioning graft after the first 30 days from after the first 30 days from Tx Tx (efficacy (efficacy evaluable evaluable patients patients -

• EFF) 94 46

EFF) 94 46 48 48 Per Per-

• protocol

protocol evaluable evaluable patients (PP) 85 patients (PP) 85 42 43 42 43 _______________________________________________________ ______________________________________________________________________________________________ _______________________________________

RESULTS RESULTS

Table 7.4-1 Patients demographic characteristics by treatment Safety population ___________________________________________________________________________________ Antibody group Steroids group N = 50 N = 51 ___________________________________________________________________________________ Age (years) N 50 51 Mean 52.0 55.0 SD 8.8 7.8 Median 51.0 56.0 Range 37 - 66 21 - 67 Age group – n (%) up to 30 0 ( 0.0%) 1 ( 2.0%) 31 to 50 24 ( 48.0%) 10 ( 19.6%) 51 to 65 25 ( 50.0%) 39 ( 76.5%) 66 or older 1 ( 2.0%) 1 ( 2.0%) Sex – n(%) Male 36 ( 72.0%) 33 ( 64.7%) Female 14 ( 28.0%) 18 ( 35.3%) Race – n(%) Caucasian 47 ( 94.0%) 51 (100.0%) Black 0 ( 0.0%) 0 ( 0.0%) Oriental 1 ( 2.0%) 0 ( 0.0%) Other 2 ( 4.0%) 0 ( 0.0%) ___________________________________________________________________________________

RESULTS RESULTS

Table 7.4-6 Recipient viral serology by treatment Safety population ________________________________________________________________________________ Antibody group Steroids group N = 50 N = 51 ________________________________________________________________________________ CMV negative 17 ( 34.0%) 12 ( 23.5%) positive 32 ( 64.0%) 36 ( 70.6%) not done 1 ( 2.0%) 3 ( 5.9%) HBsAg negative 50 (100.0%) 50 ( 98.0%) positive 0 ( 0.0%) 1 ( 2.0%) not done 0 ( 0.0%) 0 ( 0.0%) AntiHBs negative 33 ( 66.0%) 27 ( 52.9%) positive 15 ( 30.0%) 22 ( 43.1%) not done 2 ( 4.0%) 2 ( 3.9%) AntiHBc negative 30 ( 60.0%) 25 ( 49.0%) positive 17 ( 34.0%) 24 ( 47.1%) not done 3 ( 6.0%) 2 ( 3.9%) HCVAb negative 0 ( 0.0%) 0 ( 0.0%) positive 50 (100.0%) 50 ( 98.0%) not done 0 ( 0.0%) 1 ( 2.0%) EBV negative 14 ( 28.0%) 12 ( 23.5%) positive 29 ( 58.0%) 22 ( 43.1%) not done 7 ( 14.0%) 17 ( 33.3%) HSV negative 17 ( 34.0%) 13 ( 25.5%) positive 23 ( 46.0%) 16 ( 31.4%) not done 10 ( 20.0%) 22 ( 43.1%) HIV negative 49 ( 98.0%) 50 ( 98.0%) positive 0 ( 0.0%) 0 ( 0.0%) not done 1 ( 2.0%) 1 ( 2.0%)

EFFICACY EVALUATION

• The EVALUATION OF THE PRIMARY EFFICACY was

conducted on ITT population (Intention to treat ).

• From ITT population we removed the subjects who died or who

lost the graft within the first 30 days from the surgery. It is widely known that these events are mainly bound to the complications of the operation rather than to the pharmacological treatments used.

• The variable, through which the primary efficacy has been

evaluated, was death or graft loss.

EFFICACY EVALUATION

For evaluating the primary efficacy, we calculated the

following parameters at 12 months of follow-up : –

The RATE OF SUCCESSES AND FAILURES for each

• f the two treatment groups.

– The SURVIVAL PROBABILITY within each of the two treatment groups (Kaplan-Meier survival analysis). – The TREATMENT EFFECT within the two groups by using Cox Regression Model.

EVALUATION OF THE PRIMARY EFFICACY

Table 9.1 Table 9.1-

• 1

1 Rate of successes and failure by treatment and s Rate of successes and failure by treatment and sensitivity analysis ensitivity analysis Efficacy Efficacy evaluable evaluable patients patients

__________________________________________________ _______________________________________________________________________________________________ _____________________________________________ Antibody group Steroids group N = 46 N = 48 _______________________________________________________________________________________________ 12-month success of treatment 42 ( 91.3%) 42 ( 87.5%) 12-month failure of treatment 4 ( 8.7%) 6 ( 12.5%)

• f which:

death 3 ( 6.5%) 4 ( 8.3%) graft loss 1 ( 2.2%) 1 ( 2.1%) loss to follow-up 0 ( 0.0%) 1 ( 2.1%) Product-limit estimate

• f probability of success 0.910 0.875

Treatment effect from Cox model p = 0.627 _______________________________________________________________________________________________ Sensitivity analysis: lost to follow up considered as successes 12-month success of treatment 42 ( 91.3%) 43 ( 89.6%) 12-month failure of treatment 4 ( 8.7%) 5 ( 10.4%) Product-limit estimate

• f probability of success 0.910 0.894

Treatment effect from Cox model p = 0.857 _______________________________________________________________________________________________ Deaths and graft losses occurring both during the study and during the follow-up are considered

EVALUATION OF THE PRIMARY EFFICACY

• 0. 00
• 0. 25
• 0. 50
• 0. 75
• 1. 00

t t event 212m 50 100 150 200 250 300 350 400 S T R A T A : t rt = 1 C ensored t rt = 1 t rt = 2 C ensored t rt = 2

KAPLAN-MEIER Log-Rank Test P-value: 0.61 n.s.

The inversion of the trend of the two curves would need a correction for the time variable because in these cases the Log-Rank test is not very powerful. But, since the number of the occurred events is very low, this further correction would not lead to a significant difference

• f the survival

probability between the two treatment groups in any case. So we did not do this correction. RED: STEROIDS BLACK: ANTIBODY

EVALUATION OF THE SECONDARY EFFICACY

Table 9.2-2 Occurrence of BPAR and of BPAR, death or graft loss in the first six months of study by treatment ITT population _________________________________________________________________________ Antibody group Steroids group N = 50 N = 51 _________________________________________________________________________ 6-month occurrence of BPAR: yes 11 ( 22.0%) 13 ( 25.5%) no 39 ( 78.0%) 38 ( 74.5%) between-group comparison † p = 0.958 _________________________________________________________________________ 6-month occurrence of BPAR, death or graft loss yes 18 ( 36.0%) 18 ( 35.3%) no 32 ( 64.0%) 33 ( 64.7%) between-group comparison † p = 0.640 _________________________________________________________________________ † Cochran-Mantel-Haenszel test stratified by center, p value

EVALUATION OF THE SECONDARY EFFICACY

Table 9.2-3 Pure patient survival and pure graft survival by treatment ITT population _______________________________________________________________________________________________ Antibody group Steroids group N = 50 N = 51 _______________________________________________________________________________________________ 12-month pure patient survival deaths 5 ( 10.0%) 6 ( 11.8%) alive after 12 months 45 ( 90.0%) 45 ( 88.2%) censored (lost to follow-up) 0 ( 0.0%) 1 ( 2.0%) Product-limit estimate

• f 12-month survival probability 0.892

0.878 Treatment effect from Cox model p = 0.897 _______________________________________________________________________________________________ 12-month pure graft survival graft loss 3 ( 6.0%) 2 ( 3.9%) graft functioning after 12 months 47 ( 94.0%) 49 ( 96.1%) censored (death or lost to follow-up) 5 ( 10.0%) 7 ( 13.7%) Product-limit estimate

• f 12-month graft survival probability 0.937

0.957 Treatment effect from Cox model p = 0.489 _______________________________________________________________________________________________________

EVALUATION OF THE SECONDARY EFFICACY

Table 9.2-5 Logarithm of viral load (log genome Eq/ml) by visit and treatment ITT population

• ----- Measured value ------
• ---------- Change from baseline ------------

Treatment group Visit n mean median SD n† mean median SD -- 95% CI --- __________________________________________________________________________________________________________________ Antibody Baseline 16 5.31 5.65 1.76 - Day 28 16 5.82 6.29 1.25 16 0.51 0.28 1.91 -1.99 - 6.30 Month 3 16 5.96 6.35 1.32 16 0.65 0.20 2.08 -2.82 - 6.28 __________________________________________________________________________________________________________________ Steroids Baseline 24 5.24 5.62 1.43 - Day 28 24 5.37 5.55 1.43 24 0.13 0.08 1.04 -2.60 - 1.93 Month 3 24 6.03 6.59 1.97 24 0.80 0.88 1.09 -2.11 - 2.63 __________________________________________________________________________________________________________________

EVALUATION OF THE SECONDARY EFFICACY

Table 9.2-6 Distribution of patients by viral load, visit and treatment ITT population _________________________________________________________________________ Antibody group Steroids group N = 16 N = 24 _________________________________________________________________________ baseline viral load < X gen.Eq/ml 10 ( 20.0%) 15 ( 29.4%) viral load >= X gen.Eq/ml 6 ( 12.0%) 9 ( 17.6%) between-group comparison † p = 0.949 _________________________________________________________________________ 28-day visit viral load < X gen.Eq/ml 6 ( 12.0%) 16 ( 31.4%) viral load >= X gen.Eq/ml 10 ( 20.0%) 8 ( 15.7%) between-group comparison † p = 0.185 _________________________________________________________________________ 3-month visit viral load < X gen.Eq/ml 6 ( 12.0%) 6 ( 11.8%) viral load >= X gen.Eq/ml 10 ( 20.0%) 18 ( 35.3%) between-group comparison † p = 0.190 _________________________________________________________________________ † Cochran-Mantel-Haenszel test stratified by center, p value

SAFETY EVALUATION SAFETY EVALUATION

Table 10.1 Table 10.1-

• 1

1 Steroid-related adverse events Safety population ______________________________________________________________________________________________ Antibody group Steroids group N = 50 N = 51 _______________________________________________________________________________________________ Any steroid-related AE 10 (20.0%) 29 (56.9%) between-group comparison † p = 0.005 diabetes 1 ( 2.0%) 6 (11.8%) hypercholesterolemia 0 ( 0.0%) 0 ( 0.0%) hypertension 8 (16.0%) 17 (33.3%) signs and symptoms of CAD 1 ( 2.0%) 6 (11.8%) cataract 0 ( 0.0%) 0 ( 0.0%) bone necrosis 0 ( 0.0%) 0 ( 0.0%) fractures 0 ( 0.0%) 0 ( 0.0%) _______________________________________________________________________________________________ † Cochran-Mantel-Haenszel test stratified by center, p value

SAFETY EVALUATION SAFETY EVALUATION

Table 10.3-3 Laboratory results and their change from baseline by treatment group at endpoint - Biochemistry Safety population

• ---------------- Post baseline ----------------

Treatment -- Baseline (Day 0) -

• ---- At endpoint ----

Change from baseline Variable group n† mean SD median mean SD median mean SD median ________________________________________________________________________________________________________________________ Serum creatinine (mg/dl) Antibody 49 6.9 24.7 0.8 3.2 13.5 1.1 -3.7 20.8 0.3 Steroids 49 8.2 29.7 0.8 7.5 29.8 1.1 -0.7 25.6 0.2 ________________________________________________________________________________________________________________________ Total bilirubin (mg/dl) Antibody 49 6.1 11.4 2.5 3.7 6.8 1.3 -2.4 12.4 -0.5 Steroids 48 5.8 15.6 1.9 3.3 8.7 1.3 -2.5 7.9 -0.5 ________________________________________________________________________________________________________________________ AST (SGPT - U/l) Antibody 48 124.6 86.2 109.5 129.1 181.6 54.5 4.5 203.2 -45.0 Steroids 48 106.3 63.4 91.0 82.1 102.0 48.5 -24.2 116.8 -30.0 ________________________________________________________________________________________________________________________ AlT (SGOT - U/l) Antibody 48 96.0 74.5 82.5 111.0 151.9 61.5 14.9 163.3 -13.5 Steroids 50 81.0 50.5 73.0 84.1 91.0 50.0 3.1 100.5 -14.5 ________________________________________________________________________________________________________________________ Gamma GT (U/l) Antibody 42 62.6 58.5 49.5 122.5 131.6 51.0 59.9 131.6 9.0 Steroids 43 68.7 61.7 42.0 164.6 312.5 63.0 95.9 314.2 20.0 ________________________________________________________________________________________________________________________ Alkaline phosphatase (U/l) Antibody 42 235.9 150.9 212.0 253.4 173.8 196.5 17.5 221.0 19.0 Steroids 42 234.0 142.8 208.5 353.9 665.9 193.0 119.9 592.8 0.0 ________________________________________________________________________________________________________________________ † Number of subjects with both baseline and endpoint values

CONCLUSIONS CONCLUSIONS

• After evaluating the results obtained in this research project,

we have not statistical evidences which prevent us from doing the following considerations:

The studied antibody has a THERAPEUTIC EFFECT

AS GOOD AS THE THERAPEUTIC EFFECT OF THE STEROIDS in the long-term prevention of the graft rejection and of the death of the subject.

The antibody has SYSTEMIC ADVERSE EFFECTS which

are SIGNIFICANTLY LOWER than the classical therapy with corticosteroids or which are ABSENT.

The antibody also showed positive indications on the

CONTROL OF VIRAL REPLICATION and this effect might lead to a reduction of the occurance of hepatitis C, preserving the graft’s integrity.