Clinical Study Report

1 Final Report , version , July 22th ,2010 - Report Clinical TRIAL NO: FG-506-02-IT-01 Page 1 of 73 AN OPEN, MULTICENTRE, RANDOMISED, PARALLEL GROUP Study TO COMPARE IN MARGINAL OLD-FOR-OLD RENAL TRANSPLANT PATIENTS THE SAFETY AND EFFICACY OF TWO TREATMENTS: SEQUENTIAL MYCOPHENOLATE MOFETIL / DELAYED TACROLIMUS PLUS STEROIDS VS TACROLIMUS PLUS MYCOPHENOLATE MOFETIL IN PATIENTS REQUIRING INDUCTION WITH ANTI-IL2 MONOCLONAL ANTIBODY SHORT TITLE: TIGRE DOMATA (Trial Italiano Gestione REni DOnatori MArginali in Trapiantati Anziani) Clinical TRIAL NO: FG-506-02-IT-01 EudraCT Number: Clinical Study Report Study Drug Name: Tacrolimus (FK 506) Indication: Renal transplant Document Number/MGC Number: FG-506-02-IT-01 Date of Document: May 26th ,2004 Study Initiation Date: 3rd Quarter 2004 Study Completion Date: 1st Quarter 2008 Responsible Officer or Designee: Dr.

2 And Dr. , Sponsor: Original sponsor was Fujisawa GmbH and following a company merger this became Astellas Europe. This Study was performed in compliance with Good Clinical Practice (GCP). Final Report , version , July 22th ,2010 - Report Clinical TRIAL NO: FG-506-02-IT-01 Page 2 of 73 Table of Contents 1 ETHICS 11 2 INVESTIGATORS AND Study ADMINISTRATIVE STRUCTURE 11 3 INTRODUCTION 12 Background Information 12 Rationale for the Study 15 3 Study OBJECTIVES 16 5

3 INVESTIGATIONAL PLAN AND METHODS 17 Study Design and Plan Description 17 Overall 17 Rationale for Study Design 18 Amendment and Administrative Change Summary 18 Selection of Study Population 19 Screening Assessments 19 Inclusion Criteria 19 Exclusion Criteria 19 Criteria for Withdrawal or Discontinuation 20 Treatments 21 Treatments Arm 1 21 Treatments Arm 2 23 Treatment of rejection

4 25 Identity of Investigational Products 25 Method of Assigning Subjects to Treatment Groups 25 Blinding 26 Treatment Compliance 26 Prior and Concomitant Medications and Therapies 26 Assessments, Endpoints, and Appropriateness of Measurements 26 Overview of Schedule of Procedures 26 Efficacy 28 diagnosis and grading of rejection episodes 28 Classification of acute rejection episodes 28 Safety 28 Adverse events 28 Serious adverse

5 Events 28 Final Report , version , July 22th ,2010 - Report Clinical TRIAL NO: FG-506-02-IT-01 Page 3 of 73 Relationship to Drug 29 Severity of AE 30 Detection , Reporting and Responsibilities 30 Blood Pressure and Body Weight 31 Laboratory Examinations 31 Additional Measurements and Ascertain Data 32 Whole Blood Tacrolimus Trough Level Measurements 32 Other Additional Data 32 Statistical Methods 33 Planned Sample Size

6 33 Populations for Analysis 33 Statistical Methodology 34 Definitions, Data Conversions, and Handling of Missing Data 34 General Time Definition 34 Definition of Days, Weeks and Months and Time Windows 34 Handling of Dropouts and Missing Values 35 General Calculation Rules 36 Demographics, Other Baseline Characteristics.

7 And Prior and Concomitant Medications 37 Efficacy 37 Primary Endpoint Definition and Method for Analysis 37 Secondary Efficacy and Safety Endpoints 37 Safety 40 Coding of Adverse Events 40 Analysis of Adverse Events 40 Laboratory Data 41 Diabetes 41 Concomitant medications of special interest 41 Changes from Planned Analyses 41 Interim Analyses 42 Data Quality Assurance and Data Issues 42 6 RESULTS.

8 Study POPULATION 42 Disposition of Subjects and Analysis Set 42 Number and Distribution of Patients 43 Final Report , version , July 22th ,2010 - Report Clinical TRIAL NO: FG-506-02-IT-01 Page 4 of 73 Reasons for Withdrawal 44 Protocol Deviations 44 Major Protocol Deviations 44 Demographics and Other Baseline Characteristics 45 Demographics and Viral Status at Baseline 45 Primary diagnosis 47 Secondary diagnosis

9 48 Medical History 48 Donor Organ Demographics and donor viral status 48 Concomitant Therapies 49 Overall Concomitant Medication Use 49 7 RESULTS: TREATMENT COMPLIANCE AND Study DRUG EXPOSURE 50 Treatment Compliance 50 Administration of Study Drugs, Corticosteroids, and Anti-Rejection Therapy 50 Tacrolimus Administration 50 MMF Administration 51 Corticosteroid Administration 52 Basiliximab Administration 53 8 RESULTS.

10 EFFICACY 54 Efficacy/ Clinical Evaluation Results 54 Primary Endpoint [creatinine clearance] 54 Secondary Efficacy Endpoints [ rejections] 55 Graft loss and death 57 Efficacy/ Clinical Evaluation Conc