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
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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
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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
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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
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SYNOPSIS
STUDY TITLE ATG Fresenius observational study on the prevention of GvHD in allogeneic stem cell transplant patients ABBREVIATED TITLE ATOS (ATG OBSERVATIONAL STUDY) STUDY NUMBER NIS-ATG-01 INDICATION/ ATG-Fresenius S (ATG-F) is indicated for prevention of graft-versus-host MAIN DIAGNOSIS disease (GvHD) in combination with standard Cyclosporine A (CyA) / Methotrexate prophylaxis in adults with haematological malignancies receiving stem cell transplantation from matched unrelated donors. STUDY OBJECTIVES This study will capture the use of ATG-F in day to day clinical practice and investigate the patients’ benefit resulting from GvHD prophylaxis with ATG-F in the context of allogeneic hematopoietic stem cell transplantation (SCT), in terms of safety and tolerability, freedom from GvHD, freedom from relapse, survival, and quality of life. STUDY DESIGN Prospective national multicenter non-interventional study (NIS, observational study). Enrolled patients will be evaluated and treated according to summary of Product Characteristics (SPC-Fachinformation) and physicians’ decision. For observational studies no study specific visits will be scheduled. Documentation will be done at the routine visits according to center standards. Data will be collected at: Baseline after 100 days after 12 months If a patient cannot be seen at study site the investigator will ask for physician letters from patients’ family doctor or outpatients’ physician according to medical practice. ENDPOINTS Primary endpoint: GvHD and relapse- free survival, defined as survival free of severe GvHD and free of relapse Secondary endpoints: Engraftment aGvHD cGvHD Relapse Relapse mortality Non-relapse mortality Disease-free survival Overall survival New malignancies Immunosuppressive therapy Quality-of-life Resource consumption Safety: Adverse Drug reactions (ADR), serious ADR (SADR), severe infections st TIMETABLE Enrolment of first patient (FPFV) 1 quarter 2013 Enrolment of last patient 1st quarter 2015 End of trial for last patient (LPLV) 1st quarter 2016 Final statistical analysis 4th quarter 2016 Planned duration of follow-up 12 months
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SAMPLE SIZE A total of 150 patients will be included in this study. STATISTICAL ANALYSIS GvHD and relapse- free survival, defined as survival free of severe GvHD and free of relapse Incidence & time to engraftment Incidence & time to aGvHD Incidence & time to cGvHD Incidence & time to relapse Incidence & time to relapse mortality Incidence & time to non-relapse mortality Disease-free survival Overall survival Quality-of-life Resource consumption INCLUSION CRITERIA Patients, 18-65 years of age Written informed consent Patients suffering from hematological malignancies Patients designated to undergo allogeneic bone marrow or peripheral blood stem cell transplantation from matched unrelated donors who will receive GvHD prevention according to ATG-F SPC Physician’s therapy decision is independent from inclusion EXCLUSION CRITERIA Patients who formerly underwent transplantation including previous autologous transplantation
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1. Introduction
Allogeneic hematopoietic stem cell transplantation (HSCT) is increasingly used worldwide as a curative therapy for malignant and non malignant hematological disorder. Chronic graft- versus-host Disease (GvHD) is the leading cause of non-relapse mortality (NRM) and of morbidity following allogeneic HSCT. Chronic GvHD is a multiorgan disease ressembling autoimmune disorder such as scleroderma or systemic lupus. Incidence and prevalence of cGvHD may be related to risk factors like patient’s age, donor age, use of peripheral blood stem cells instead of bone marrow, matching degree, etc. Altogether chronic GvHD represents one of the most challenging complication after allogeneic HSCT, to date.
Anti-T-cell globulins (ATGs) might lower the incidence of GvHD. The ATG Fresenius trial group conducted a prospective, randomised, multicentre, open-label, phase III trial to compare standard GvHD prophylaxis with cyclosporin and methotrexate with or without anti- Jurkat ATG-Fresenius S (ATG-F) (Finke et al., 2009 (2), Socié et al., 2011 (4), Finke et al., 2012 (3)). In this clinical trial it could be shown that the addition of ATG-F to GvHD prophylaxis with cyclosporin and methotrexate resulted in decreased incidence of acute and chronic GvHD without an increase in relapse or non-relapse mortality, and without compromising overall survival. The use of ATG-F is safe for patients who are going to receive a haematopoietic cell transplantation from matched unrelated donors (Finke et al., 2009 (2)).
The study and referring study results were the basis for obtaining the marketing authorisation in Germany for the prevention of GvHD for stem cell transplant patients. This non interventional study should evaluate patients’ outcome and benefit on a broad basis in day to day clinical practice without the selective measures of a clinical trial.
2. Purpose of study
The aim of this NIS is to obtain further evidence on patients benefit resulting from ATG-F GvHD prophylaxis in the context of allogeneic HSCT. ATG-F recently was granted a marketing authorisation by the Paul Ehrlich Institute (PEI), so this NIS will give the possibility to extend experience with ATG-F and to observe its effects under routine clinical conditions. The patient data will be collected under real-life conditions, deeper insights of the clinical relevance of the ATG-F use are expected. Special interest is drawn to the: freedom from GvHD freedom from relapse survival quality of life resource consumption safety data
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The results obtained will be contrasted to results of the ATG-F treatment arm in study AP-AS-21-DE (see section 18 References)
3. Study population and inclusion criteria
Adult patients who suffer from haematological malignancies undergoing HSCT from unrelated donor who are receiving ATG-Fresenius S GvHD prophylaxis are eligible if they get therapeutic therapy according to the Summary of Product characteristics (SPC- Fachinformation) and if they agree to sign the patient informed consent form.
Therapeutic indication according to SPC: ATG-Fresenius S is indicated for prevention of graft-versus-host disease (GvHD) in adults with haematological malignancies following stem cell transplantation from matched unrelated donors in combination with standard Cyclosporin A/methotrexate prophylaxis.
Posology and method of administration according to SPC: As part of myeloablative conditioning regimens for stem cell transplantation, the recommended dose is 20 mg/kg/d of ATG-Fresenius S, usually starting from day -3 to day -1 prior to HSCT.
The patients should only be considered for participating in this non-interventional study AFTER the decision was made to start therapy with ATG-F!
3.1. Inclusion criteria
Male and female patients, 18-65 years of age Written informed consent Patients suffering from hematological malignancies Patients designated to undergo allogeneic bone marrow or peripheral blood stem cell transplantation from matched unrelated donors who will receive GvHD prevention according to ATG-F SPC Physician’s therapy decision is independent from inclusion
3.2. Exclusion criteria
Patients who formerly underwent transplantation including previous autologous transplantation
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4. Study design
This is a prospective, national, multicenter non-interventional study (NIS).
No control group will be included for comparison.
5. Study duration and timetable
Study duration approximately 4 years: 2 years recruitment, 1 year follow-up (FU), 1 year data cleaning, analysis and reporting
Enrolment of first patient (FPFV) 1st quarter 2013 Enrolment of last patient 1st quarter 2015 End of study for last patient (LPLV) 1st quarter 2016 Final statistical analysis 4th quarter 2016 Planned duration of follow-up 12 months
6. Participating centers
For representativeness reasons most of the German stem cell transplantation sites will be contacted and asked for participation in this study. Approximately 20 sites will be approached to participate in this study. A list of participating sites and investigators will be provided by the Sponsor and updated regularly to the Federal Joint Committee of Statutory Health Insurance (FJCSHI) and the Association of Statutory Health Insurance Physicians (ASHIP).
7. Conduct of the study
7.1. Study Procedure
In order to avoid selection bias, physicians are asked to include all patients fulfilling the inclusion and exclusion criteria in a consecutive way.
The site will complete and file separate screening and enrolment logs. Each patient will be identified in the study by a consecutive Patient Number (see chapter 9). The site will fax a separate registration form to Fax No. 0761 270-73770 before enrollment. Overall patient lists will be maintained by the CTU.
After informed consent is obtained, two clinical visits will be performed according to clinical routine: one 100 days and a second one 12 months after HSCT.
For non-interventional studies scheduled study visits besides the routine visits are not allowed. Thus, patients should not be invited for visits which do not arise from the routine work.
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7.2. Baseline Evaluation
- DRST (Deutsches Register für Stammzelltransplantation) Registry ID - Demographics patient (age, sex, weight, height) and donor (age, sex) - Date of primary diagnosis of current hematologic malignancy, - Date of HSCT (= day 0) - Stem cell source - Type of primary disease; disease status - HLA-match patient/donor (HLA-A, -B, -C, -DQB1, -DRB1: Match (2-digit), Match (4- digit), Mismatch) - CMV and EBV status (patient/donor) - Conditioning Regimen - ATG-F administration (dates, doses and infusion time) - Ex-vivo T-cell depletion (Yes/No) - Karnofsky-Index - Employment status: “Working”, “retired”, “not working” (independent of actual sickness leave)
7.3. Evaluation at day 100
- Karnofsky-Index - EQ-5D - CMV prophylaxis/monitoring and EBV monitoring (Yes/No)
7.4. Evaluation at month 12
- Karnofsky-Index - EQ-5D
- Photopheresis treatment, number of sessions within 12 months
- Number of visits to the outpatient clinic (at the hospital where the HSCT was performed) within 12 months
- Hospital stays, start and stop dates within 12 months and thereof number of days in intensive care unit (ICU)
- Employment status: “Working”, “retired”, “not working”; if working in principle: “duration of sickness leave within the last 12 months”
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7.5. Continuous evaluation
Evaluation of the parameters below has to be performed continuously, last check at month 12: - Date of the first of three consecutive days with a platelet count > 50,000 /l and without transfusions
- Date of the first of three consecutive days with a ANC > 1,000 /l - aGvHD: max grade, date of onset; maximum severity of symptoms at skin, intestinal tract and liver - cGvHD: max grade (limited/extensive) and NIH (Filipovitch et al., 2005 (1)), date of onset - Relapse: date of relapse diagnosis - New malignancies (particularly PTLD but also others), diagnosis and date of diagnosis - Survival; date and principal cause of death - Immunosuppressive therapy, drug (generic drug name or brand name), duration (start and stop date)
- ADRs, SADRs, severe infections (for definition of severe infections please refer to section 8)
7.6. NIS Flow Chart
Even if no specific visits besides routine visits are required mandatory, patients will routinely have follow up visits 100 days and 12 months after HSCT. The referring data which are collected at the respective visits are shown in Table 1.
Table 1: Flow Chart Baseline Day 100 Month 12 + according to +/- according to center standard center standard Informed consent X DRST registry X Demographics (patient/donor) X Date of primary diagnosis of current X hematologic malignancy Date of HSCT and stem cell source X Primary disease data (type and status) X HLA-match (patient/donor) X
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Baseline Day 100 Month 12 + according to +/- according to center standard center standard CMV-, EBV-status (patient/donor) X Conditioning regimen X ATG-F administration X Ex-vivo T-cell depletion X Karnofsky Index X X X Employment status X X CMV-prophylaxis/monitoring, EBV-monitoring X EQ-5D X X Engraftment, date of first lab showing platelets > 50,000 /l X X ANC > 1,000 /l Relapse, new malignancies, survival X X aGvHD X X cGvHD X Duration of sickness leave X Photopheresis Treatment (number of X sessions) within 12 months Number of visits to outpatient clinic X Hospital stays X Immunosuppressive therapy X X ADRs, SADRs, severe infections X * X X * starting from the first administration of ATG-F
8. Documentation and Reporting of Adverse Drug Reactions
The purpose of the documentation of adverse drug reactions (ADRs) is to generate scientific data of potential clinical or public health importance. The obligation to document and report side-effects (ADRs) independent of clinical trials is laid down in the Medical Association’s professional code of conduct (Berufsordnung der Ärztekammer, I §6) and the German Medicines Law (AMG §63 b).
Therefore, adverse drug reactions for which a causal relationship to the applied study drug is at least a reasonable possibility as well as severe infections independent of their causal relationship to the study drug will be documented by the participating site on specific ADR CRF-pages. Severe infections are defined according to CTCAE Version 4.0.
The ADR CRF-pages need to be faxed to the Clinical Trials Unit (CTU) on a weekly basis. In addition, serious adverse drug reactions (SADR) have to be reported to the sponsor on a separate SADR reporting form at least on a weekly basis.
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8.1. Definitions
8.1.1. Adverse Drug Reaction
An ADR, also referred to as side-effect, is a harmful and unintended reaction to a medicinal product which occurs at dosages that are normally used in humans for prophylaxis, diagnose and therapy of diseases or for the recreation, correction or alteration of a physiological function.
In case of an ADR, in contrast to an adverse event, a relationship is assumed between the occurred ADR and the medicinal product, due to indications, evidence or arguments that make an involvement of the medicinal product in the occurrence of the ADR plausible or an involvement of the applied medicinal product is at least believed.
The deficient efficacy of a medicinal product does not fulfill the definition of an ADR. The same is true for symptoms that definitely originate from the underlying or a concomitant disease of the patient including the progression thereof.
The term „death“ is not sufficient for the description of an ADR. Death is the consequence or respectively the outcome of a sickness that in case of an ADR must be classified as serious (see section 8.1.2) and must be documented and reported accordingly.
8.1.2. Serious Adverse Drug Reaction (SADR)
The seriousness of an ADR is mainly defined by the result of the sickness. Any ADR that meets one of the following criteria is considered to be serious:
The ADR which
results in death is immediately life-threatening requires in-patient hospitalization or prolongs existing hospitalization results in persistent or significant disability/incapacity is a congenital anomaly/birth defect
Life-threatening refers to an ADR that, at the time point of the ADR, constituted a fatal risk for the patient. It does not refer to an ADR that hypothetically could result in death if it develops a major severity and in certain circumstances had led to complications.
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Additionally, medically significant ADRs should be classified as serious if they are not immediately lethal or life-threatening or lead to in-patient hospitalization but substantially affect the patient. Medically significant are ADRs also if they require an intervention / treatment in order to prevent a condition that corresponds to one or more of the above mentioned seriousness criteria.
The review of ADRs regarding the existence of a seriousness criterion has to be clearly distinguished from the determination of the severity of an ADR. “Serious” and “severe” are not to be utilized synonymously. The seriousness of an ADR is defined according to the above mentioned criteria. The severity of an ADR, also referred to as intensity, is described by the classification into CTCAE grade 1-5 according to the Common Terminology Criteria for Adverse Events of the NCI (NCI-CTCAE).
8.2. Procedure
8.2.1. Documentation of ADRs and severe infections
All ADRs and severe infections that are observed in line with the NIS are documented in the observation form (CRF) by the physician in charge. For all ADRs and severe infections a short description (symptom or preferably diagnosis), the start and the stop date, the intensity according to NCI-CTCAE grade, the relationship to study drug, the action taken with regard to study drug (ATG-Fresenius S), the outcome and the evaluation if serious - yes/no - shall be recorded.
8.2.2. Documentation and reporting of SADRs
Each ADR is reviewed by the physician in charge with regard to the existence of one or more seriousness criteria. For each SADR the physician in charge completes a SADR reporting form in addition to the documentation in the observation form (CRF). On the reporting form at least the following information must be included for the initial reporting (minimal criteria):
an identifiable patient (gender and age) a description (symptom or preferably diagnosis) of the SADR an administered suspicious medicament (ATG-Fresenius S) an identifiable reporting source, i.e. name and contact details of the reporting physician
Additionally, the following information should be entered onto the SADR reporting form or handed in as soon as possible, respectively:
start and stop date of the SADR
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treatment information of ATG-Fresenius S seriousness criterion severity (intensity) other potentially causal reasons for the occurrence of the SADR outcome concomitant diseases (in particular information concerning the underlying hematological malignancy) and concomitant medication detailed description of the course of the SADR including relevant laboratory values treatment of the SADR
8.2.3. Timelines and contact details for ADR and SADR reporting
Non-serious adverse drug reactions will be reported to the sponsor by the CTU on a monthly basis in form of a line listing. In order for the CTU to generate these line listings, the physician in charge must fax the ADR CRF-page(s) to the CTU on a weekly basis.
The physician in charge must fax the ADR CRF-page(s) to Clinical Trials Unit Freiburg once a week 0761 270-74390
In parallel, the physician in charge must inform Fresenius Biotech about SADRs at least on a weekly basis, preferably when reviewing and faxing the ADR CRF-page(s). For each SADR a SADR reporting form must be completed and sent to Fresenius Biotech Drug Safety either by fax or by email.
SADRs have to be reported to Fresenius Biotech at least on a weekly basis:
Fresenius Biotech GmbH Drug Safety
Fax: 06172 608 390 130
E-Mail: [email protected]
8.2.4. Time period for documentation and reporting
Severe infections, ADRs and SADRs shall be documented in the CRF starting with the first administration of ATG-Fresenius S and until the “month 12” visit of the patient (i.e. during the
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After this time period the common responsibilities concerning the spontaneous reporting of side-effects apply to the physicians in charge.
8.2.5. Follow-up information on SADRs, ADRs and severe infections
Severe infections, ADRs and SADRs shall be followed up by the physician in charge until the documentation in the CRF is complete. The same applies to the reporting of SADRs to the sponsor. In order to complete missing information regarding a SADR, the drug safety department of Fresenius Biotech will send requests to the physician in charge which he must return as soon as possible and as completely answered as possible.
9. Data Collection
All study relevant data will be collected on paper CRFs which are created for this purpose. Patient data will be pseudonymized and completed and signed CRFs will be sent to the Clinical Trials Unit Datamanagement.
Each patient will be identified in the study by a Patient Number (Patient No.) that is assigned when the patient is first enrolled for screening and is retained as the primary identifier for the patient throughout entire participation in the study. The Patient No. consists of the Centre Number (Centre No.) as assigned by the Sponsor to the study site with a sequential patient number suffixed to it, so that each patient is numbered uniquely across the entire database.
Besides the pseudonymization code the patients DRST (Deutsches Register für Stammzelltransplantation) will also be entered on the CRF. For scientific reasons later comparisons and analyses with the DRST database should be possible. The patient will be informed about this option accordingly.
10. Quality Measurements
The Clinical Trials Unit study team will be trained for this study. Clinical Trials Unit will maintain team responsibility and training lists. The sites will be informed and instructed by well-trained Clinical Research Associates (CRAs).
10.1. Monitoring
Monitoring will be part of the quality management for this NIS.
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Before study start the investigator will be informed about the observational plan. The designated CTU-CRAs will initiate the sites via phone before enrollment of the first patient into the NIS. During the trial, the monitor will be in regular contact with the sites and visit a certain number of sites at least once during the NIS to check the completeness of patient records, the accuracy of entries on the CRFs, the adherence to the observational plan and to Good Clinical Practice/national regulatory requirement.
Key trial personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the trial, consisting of case and visit notes (hospital or clinic medical records) containing demographic and medical information, and the results of any other tests or assessments. All information recorded on CRFs must be traceable to source documents in the patient's file. The investigator must also keep the original signed informed consent form (a signed copy is given to the patient). All information in original records and certified copies of original records of clinical findings, observations or other activities in a clinical trial are necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies) and can be said to be the first place where information is recorded/captured.
Source data verification (SDV) will be performed in order to verify the accuracy and completeness of the entries on the case report form (CRF) by comparing them with the source data, and to ensure and increase the quality of the data. All subject related data have to be entered in the medical record. In case of a separate source document (e.g. laboratory report), this has to be added to the medical record.
The investigator must give the monitor access to all relevant source documents to confirm their consistency with the CRF entries. Detailed monitor procedures will be described in the study specific Monitor Manual.
11. Data Management
The data management will prepare paper Case Report Forms (CRFs) and the clinical database. Details on data management (procedures, responsibilities, record keeping, data validation and data correction) will be described in a Data Management Plan. During the study, the performance of data management and any deviations from the Data Management Plan will be documented in a Data Management Report. At the Clinical Trials Unit all data will be entered by double key data entry into the study specific database which is part of the data management system DAMAST. The data management system DAMAST is a validated system running under Linux, SAS Version 9.2. SAS software will also be used to review the data for completeness, consistency and plausibility. All programs will be validated and open
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ATOS: NIS-ATG-01 Observational Plan questions will be resolved by queries. Data in the clinical database will be checked and queries will be sent to the sites promptly according to the data flow.
12. Statistical Planning and Analysis
The primary endpoint is the GvHD and relapse-free survival, defined as survival free of severe GvHD (aGvHD III-IV or extensive cGvHD) and free of relapse. Secondary endpoints are engraftment of ANC and platelets, aGvHD, cGvHD, relapse, relapse mortality, non- relapse mortality (NRM), disease-free survival (DFS), overall survival (OS), new malignancies, immunosuppressive therapy, quality-of-life, resource consumption, safety data (ADR,SADR, severe infections). The probability of GvHD and relapse-free survival, the incidences of engraftment, aGvHD, cGvHD, relapse, relapse mortality, NRM, the probabilities of DFS and OS, and the probabilities of survival under immunosuppressive therapy and of survival free of immunosuppressive therapy will be estimated. For the analysis of time-to-event variables, for which no competing events have to be considered, i.e. time to the combined endpoint aGvHD III-IV, extensive cGvHD, relapse, death, DFS time (time from Tx to the first event of failure: relapse or death) and OS time, the following statistical methods will be used. The probability of an event over time will be estimated by the Kaplan-Meier method. The time-to-event will be compared between patient groups with Cox regression models using two-sided Wald tests. As an estimate of the size of the effects in these models, the hazard ratios (HRs) will be calculated with corresponding two-sided 95% confidence intervals. For the analysis of time-to-event variables, for which competing events have to be considered, e.g. time to engraftment or aGvHD or cGvHD with relapse/death as competing event, time to relapse with NRM as competing event, time to relapse mortality with NRM as competing event, time to NRM with relapse as competing event, the following statistical methods will be used. The probability of event over time will be estimated by cumulative incidence rates. The time-to-event will be compared between patient groups with Cox regression models for the event-specific hazard functions of competing events using two- sided Wald tests. As an estimate of the size of the effects in these models the HRs will be calculated with corresponding two-sided 95% confidence intervals.
The probabilities of survival under immunosuppressive therapy and of survival free of immunosuppressive therapy over time will be estimated with the Aalen-Johansen estimator. The effects of the following prognostic factors on outcome will be analyzed in univariate and multiple Cox regression models: patient age, donor age, patient and donor sex, patient and donor CMV status, type of primary disease, disease status, conditioning regimen, time from
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ATOS: NIS-ATG-01 Observational Plan primary diagnosis of current disease to transplantation, stem cell source, and extent of GvHD prophylaxis. The outcome of patients will be compared to the outcome of the patients in the ATG-F treatment arm in study AP-AS-21-DE (2),(3),(4) using Cox regression models including relevant prognostic factors for adjustment. Other secondary endpoints (new malignancies, immunosuppressive therapy, quality-of-life, resource consumption) will be analyzed descriptively. The number and percentage of patients experiencing adverse drug reactions, serious adverse drug reactions and severe infections will be presented to evaluate the tolerability. A sample size of 150 patients was deemed feasible for recruitment within the planned time period and necessary to obtain precise results. With 150 patients, the incidence of an event can be estimated with a minimal precision of ± 0.08 (maximal width of 95%-confidence interval if incidence is 0.5). The power for the evaluation of prognostic factors is as follows. With respect to an endpoint with an incidence of 0.1 (0.3, 0.5), leading to 15 (45, 75) events, a binary prognostic factor with a prevalence of 0.5 can be detected with a power of 0.8 when its effect corresponds to a HR of 4.3 (2.3, 1.9), respectively.
13. Data Protection and Informed Consent
The pertinent provisions on data protection must be fully adhered to.
The patients will be informed of the purpose and extent of the trial, collection and use of personal and medical data. Eligible patients may only be included in the trial after providing written, IEC-approved informed consent. The process of obtaining informed consent should be documented in the patient source documents. The date when a patient’s Informed Consent was actually obtained will be captured in their CRFs.
Sponsor will provide investigators in a separate document with a proposed Informed Consent Form (ICF) that is considered appropriate for this trial and complies with the ICH GCP guideline and regulatory requirements. Any changes to this ICF suggested by the investigator must be agreed to by sponsor before submission to the IEC and a copy of the approved version must be provided to the sponsor monitor after IEC approval.
13.1. Study Team and Trial Master File
The Clinical Trials Unit of the University Medical Centre Freiburg is delegated from Sponsor for Project Management, Statistics, Data Management and Monitoring. Essential Trial Documents will be filed centrally at the Clinical Trials Unit (except Drug Safety Documentation). Trial Master File (TMF) will be sent to the Sponsor after study end for central filing.
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13.2. Investigator Site File and Archiving
All investigators receive a separate investigator site file (ISF) with essential documents required for the NIS. The investigator must archive all clinical essential documents for a minimum of 10 years starting after the definite study end (= after the inclusion of the last patient). Investigator Site Files and observation forms (CRFs) will be distributed by sales representatives.
14. Patient Insurance
As this study is purely observational, a patient specific insurance coverage is not required.
15. Implementation
The study will start after formal endorsement by the responsible Ethic Committees and notification to the National Competent Authority. Study will be conducted in compliance with all regulatory requirements according the code of medical ethics (ärztliche Berufsordnung). The study will be notified to the NASHIP (National Association of Statutory Health Insurance Physicians – Kassenärztliche Bundesvereinigung), the FJCSHI (Federal Joint Committee of Statutory Health Insurance – GKV Spitzenverband) and the Association of Private Health Insurance (Verband der Privaten Krankenversicherung). The study will be registered at the DRKS (Deutsches Register Klinische Studien) before inclusion of first patient.
16. Study Report
A study report will be written within 1 year after last patient’s visit.
17. Publication
The sponsor understands the principal interest of academia in publications for scientific reasons.
Any formal presentation or publication of data collected as a direct or indirect result of this study will be considered as a joint publication by Fresenius Biotech GmbH, the investigators and the Clinical Trials Unit. Authorship will be determined by mutual agreement.
The results of the study may be presented during scientific symposia or published in a scientific journal only after review and written approval by the sponsor and the Clinical Trials Unit.
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Investigators participating in multicenter studies must agree not to engage in presentations based on data gathered individually or by a subgroup of centers before publication of the first main publication, unless this has been agreed by sponsor.
The Marketing Authorization Holder is allowed to delete confidential information. Publication issues are described in site specific contracts.
FRESENIUS BIOTECH GMBH is free to use the relevant data of the study for registration and for worldwide scientific product documentation (e.g. scientific brochures).
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18. References
(1) Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. Diagnosis and Staging Working Group Report. Biology of Blood and Marrow Transplantation. 2005 Dezember;11(12):945-956.
(2) Finke J, Bethge W, Schmoor C, Ottinger H, Stelljes M, Zander A, et al. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009;10(9):855-864.
(3) Finke J, Schmoor C, Bethge WA, et al. Prognostic Factors Affecting Outcome after Allogeneic Transplantation for Hematological Malignancies from Unrelated Donors: Results from a Randomized Trial. Biol Blood Marrow Transplant. 2012 Jun 17; [Epub ahead of print]
(4) Socié G, Schmoor C, Bethge W et al. Chronic Graft-versus-Host Disease: long term results from a randomized trial on GvHD prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood 2011; Blood (print ISSN 0006-4971, online ISSN 1528-0020)
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