ATOS: NIS-ATG-01 Observational Plan Observational Plan ATG Fresenius observational study on the prevention of GvHD in allogeneic stem cell transplant patients Short title: ATOS (ATG Observational Study) Version 01: 08th November 2012 Study number: NIS-ATG-01 Sponsor: Fresenius Biotech GmbH Am Haag 6+7 D-82166 Gräfelfing Phone: +49-89-89-88 88-0 Medical advise Universitätsklinikum Freiburg Abteilung Innere Medizin I Hugstetter Straße 55 D-79106 Freiburg i.Br. Phone: +49-761-270-33640 Study Coordination: Universitätsklinikum Freiburg Studienzentrum (Clinical Trials Unit) Elsässer Straße 2 D-79110 Freiburg i.Br. Phone: +49-761-270-77110 This observational plan contains confidential information. Circulation of this material to individuals who are not involved in the carrying out of the study or any kind of publication requires the approval of the sponsor. These limitations similarly relate to all confidential information and data which will be obtained in the future. ATOS: NIS-ATG-01 Observational Plan Declaration of Principal Investigator at local trial center Acknowledgement of receipt and notice Compound: ATG-FRESENIUS S Project-No.: NIS-ATG-01 Short Title: ATOS Title: ATG Fresenius observational study on the prevention of GvHD in allogeneic stem cell transplant patients Study Document: Observational Plan, Version 01, dated 08th November 2012 Trial centre Principal investigator of the local study center I have read this Observational Plan and agree with it. I agree to conduct the study as set out in the Observational Plan. In particular, I agree to adhere to the moral, ethical and scientific principles governing clinical research as set out in the Declaration of Helsinki in its current version and the ICH guidelines on GCP (E6) recommended for Adoption on 01 May 1996 by the ICH Steering Committee. I understand that all documentation that has not been previously published will be kept in the strictest confidence. Name / location (block letters) Date Signature Clinical Trials Unit Freiburg Version 01, 08th November 2012 5/26 ATOS: NIS-ATG-01 Observational Plan TABLE OF CONTENTS Signature page Observational Plan: Sponsor .................................................................... 2 Signature page Observational Plan: Clinical Trials Unit ................................................... 3 Signature page Observational Plan: Clinical Expert .......................................................... 4 Table of contents .................................................................................................................... 6 Abbreviations ......................................................................................................................... 8 Synopsis ................................................................................................................................. 9 1. Introduction ................................................................................................................ 11 2. Purpose of study ....................................................................................................... 11 3. Study population and inclusion criteria .................................................................. 12 3.1. Inclusion criteria ..................................................................................................................... 12 3.2. Exclusion criteria ................................................................................................................... 12 4. Study design .............................................................................................................. 13 5. Study duration and timetable ................................................................................... 13 6. Participating centers ................................................................................................. 13 7. Conduct of the study ................................................................................................. 13 7.1. Study Procedure .................................................................................................................... 13 7.2. Baseline Evaluation ............................................................................................................... 14 7.3. Evaluation at day 100 ............................................................................................................ 14 7.4. Evaluation at month 12 .......................................................................................................... 14 7.5. Continuous evaluation ........................................................................................................... 15 7.6. NIS Flow Chart ...................................................................................................................... 15 8. Documentation and Reporting of Adverse Drug Reactions .................................. 16 8.1. Definitions .............................................................................................................................. 17 8.1.1. Adverse Drug Reaction ..................................................................................................... 17 8.1.2. Serious Adverse Drug Reaction (SADR) ........................................................................... 17 8.2. Procedure .............................................................................................................................. 18 8.2.1. Documentation of ADRs and severe infections ................................................................. 18 8.2.2. Documentation and reporting of SADRs ........................................................................... 18 8.2.3. Timelines and contact details for ADR and SADR reporting ............................................. 19 8.2.4. Time period for documentation and reporting ................................................................... 19 8.2.5. Follow-up information on SADRs, ADRs and severe infections ........................................ 20 9. Data Collection .......................................................................................................... 20 10. Quality Measurements .............................................................................................. 20 10.1. Monitoring .............................................................................................................................. 20 11. Data Management ...................................................................................................... 21 12. Statistical Planning and Analysis ............................................................................ 22 13. Data Protection and Informed Consent ................................................................... 23 13.1. Study Team and Trial Master File ......................................................................................... 23 Clinical Trials Unit Freiburg Version 01, 08th November 2012 6/26 ATOS: NIS-ATG-01 Observational Plan 13.2. Investigator Site File and Archiving ....................................................................................... 24 14. Patient Insurance ....................................................................................................... 24 15. Implementation .......................................................................................................... 24 16. Study Report .............................................................................................................. 24 17. Publication ................................................................................................................. 24 18. References ................................................................................................................. 26 Clinical Trials Unit Freiburg Version 01, 08th November 2012 7/26 ATOS: NIS-ATG-01 Observational Plan ABBREVIATIONS ADR Adverse Drug Reaction ANC Absolute Neutrophil Count aGvHD Acute Graft versus Host Disease ALL Acute lymphoid leukemia AMG Arzneimittelgesetz AML Acute myeloid leukemia ATG Anti-T-Cell-Globulin ATG-F ATG-Fresenius S cGvHD Chronic Graft versus Host Disease CML Chronic myeloid leukemia CMV Cytomegalovirus CRA Clinical Research Associates CRF Case Report Form CTCAE Common Terminology Criteria for Adverse Events CTU Clinical Trials Unit (Studienzentrum) CyA Cyclosporine A DAMAST Data Management System DFS Disease Free Survical DRKS Deutsches Register Klinische Studien DRST Deutsches Register für Stammzelltransplantation EBV Epstein-Barr Virus EQ-5D EuroQol at 5 dimensions FJCSHI Federal Joint Committee of Statutory Health Insurance FU Follow Up GvHD Graft versus Host Disease HLA Human Leukocyte Antigen HR Hazard Ratio HSCT Hematopoietic Stem Cell Transplantation IC Informed Consent ICH-GCP International Conference for harmonization of Good Clinical Practice ICU Intensive Care Unit IEC Independent Ethic Committee ISF Investigator Site File MDS Myelodysplastic syndrome NCI National Cancer Institute NIH National Institute of Health NIS Non-Interventional Study NRM Non-relapse mortality OMF Osteomyelofibrosis OS Overall Survival PEI Paul Ehrlich Institute PTLD Post Transplant Lymphoproliferative Disorder RA Refractory anemia RARS Refractory anemia with ring sideroblasts RIC Reduced Intensity Conditioning SADR Serious Adverse Drug Reaction SAS Statistical Analysis System SDV Source data Verification SPC Summary of Product Characteristics TMF Trial Master File Clinical Trials Unit Freiburg Version