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Observational Study Protocol BMS-936558 CA209653 Nivolumab Page: Protocol Number: Date Revised Date: 1 CA209653 23-May-2016 20-Sep-2016 Observational Study Protocol CA209653 A NATIONAL, PROSPECTIVE, NON-INTERVENTIONAL STUDY (NIS) OF NIVOLUMAB (BMS-936558) IN PATIENTS WITH ADVANCED RENAL CELL CARCINOMA AFTER PRIOR THERAPY Revised Protocol 01 Incorporates Amendment 01 Sites: All Study Director Medical Study Specialist Arnulfstr. 29, 80636 München, Germany Telephone (office): Fax: CORDS Scientific Support Telephone (office): Email: 3 External Investigator/CRO Winicker Norimed Deutschherrnstraße 15, 90429 Nürnberg, Germany Telephone (office): +49 (0) 911 926800 Bristol-Myers Squibb Research and Development Avenue de Finlande 8, Building F – 1st Floor B-1420 Braine-l’Alleud, Belgium 3 Rue Joseph Monier, BP 325 Rueil-Malmaison Cedex, 92506, France This document is the confidential and proprietary information of Bristol-Myers Squibb Company and its global affiliates (BMS). By reviewing this document, you agree to keep it confidential and to use and disclose it solely for the purpose of assessing whether your organization will participate in and/or the performance of the proposed BMS-sponsored study. Any permitted disclosures will be made only on a confidential "need to know" basis within your organization or to your independent ethics committee(s). Any other use, copying, disclosure or dissemination of this information is strictly prohibited unless expressly authorized in writing by BMS. Any supplemental information (eg, amendments) that may be added to this document is also confidential and proprietary to BMS and must Revised Protocol No. 1 Date: 20-Sep-2016 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab be kept in confidence in the same manner as the contents of this document. Any person who receives this document without due authorization from BMS is requested to return it to BMS or promptly destroy it. All other rights reserved. Replace all previous version(s) of the protocol with this revised protocol and please provide a copy of this revised protocol to all study personnel under your supervision, and archive the previous versions. Revised Protocol No. 1 Date: 20-Sep-2016 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab DOCUMENT HISTORY Document Date of Issue Summary of Changes Revised Protocol No. 01 20-Sep-2016 Incorporates Amendment 01 Amendment 01 20-Sep-2016 Title - “locally … or metastatic” deleted from Title and throughout Study Director - Change of Study Director Synopsis, Objectives - Title and throughout: “locally … or metastatic” deleted - Objectives: Wording of indication adapted to reflect approved indication (“locally … or metastatic” deleted”) - Added: Characteristics of AE (such as median time to onset, median time to resolution, grade at onset) Section 1.1, Rationale - Addition of efficacy data of the 025 study Section 2.2, Secondary Objectives - Characteristics of AEs added Section 3.1, Overview of Study Design - AE reporting rule deleted, referenced to AE section Section 3.2.1, Inclusion Criteria - Inclusion criteria regarding histological/cytological confirmation and prior treatment decision clarified Section 3.2.2, Exclusion Criteria - Added that “Patients that have been treated curatively more than 5 years ago with no evidence of recurrence and prostate cancer patients in active surveillance can be included.” Section 3.3.1, Patient Reported Outcome - Reporting source (paper) clarified - Requirement to screen PROs for AEs deleted as per applicable BMS policy Section 3.3.3, Patient Data - Reference to AE section added - Reference to eCRF deleted as specified in referenced AE section - Requirement of MedDRA coding and re-coding clarified and specified Section 3.4.1.1, Clinical Outcomes - Table 3.4.1.1-1: Reference to irRC deleted - Table 3.4.1.1-1: Added entry for Duration of response Section 3.4.1.2, Socio-Demographics and Clinical Characteristics - Table 3.4.1.2-1: ECOG performance score replaced by Karnofsky Revised Protocol No. 1 Date: 20-Sep-2016 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab Performance score Reference to MSKCC and IMDC risk scores deleted Diagnostic procedures adapted, Laparotomy/ laparoscopy, core biopsy, fine needle aspiration deleted, malignant ascites/pleural effusion deleted as references elsewhere Added: “Ultrasound, Conventional x-ray, Bone scintigraphy” Other prognostic characteristics deleted Histological subtypes adapted ECOG deleted Biomarkers deleted Co-morbidities adapted Section 3.4.1.3, Treatment Patterns - Table 3.4.1.3-1: Interventional Therapy deleted - Table 3.4.1.3-3: Title adapted, Surgical treatment added Section 3.4.1.4, Incidence Rate, Severity, and Management of AEs - NCI CTCAE Grading System version corrected (4.8 to 4.0) - Requirements for MedDRA re-coding (interim analysis if deemed necessary, and final analysis) clarified - Table 3.4.1.4-1: NCI CTCAE Grading System version corrected, variable ‘AE characteristics’ added, Variable’ Characteristics, such as median time to onset, median time to resolution, grade at onset’ added. Section 3.4.2, Exposure/Independent Variables of Interest - Deleted “Percentage of patients receiving monotherapy or combination therapy” - Deleted “first” from “Percentage of patients receiving nivolumab as first-, second-, or third-line therapy” - ECOG replaced by Karnofsky - Mutational status deleted - IMDC risk score added - Wording of patients with prior radiotherapy adapted, added: “to primary tumor or brain or other sites of metastases” Section 3.4.3, Other Co-variates/Control Variables - Table 3.4.3-1: Changed “lung cancer” to “renal cancer” Section 6.2.3, External Advisory/Steering Committee - Changed external steering committee to consist of approximately 3 to 4 external health care professionals Section 7.1, Adverse Event Collection and Reporting - Pregnancy added Section 7.2, Adverse Event Collection and Reporting - Wording adapted to reflect focus of the study on treatment related AEs and to define reporting periods Revised Protocol No. 1 Date: 20-Sep-2016 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab Section 7.2.1, Serious Adverse Event Collection and Reporting - Wording adapted to reflect reporting periods - Contact details for submission of pregnancies modified according to current study reporting procedures. Section 7.2.2, Non-serious Adverse Event Collection and Reporting - Wording adapted to reflect reporting periods Please maintain a copy of this amendment with your protocol. Please provide a copy to your Investigational Review Board / Ethics Committee, unless agreed otherwise with BMS. Original Protocol 23-May-2016 Not applicable Revised Protocol No. 1 Date: 20-Sep-2016 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab SYNOPSIS. Observational Study Protocol CA209653 Protocol Title: A National, Prospective, Non-Interventional Study (NIS) of Nivolumab (BMS-936558) in Patients with Advanced Renal Cell Carcinoma after Prior Therapy Department: Medical Department Germany Objective(s): The primary objective of this study is, among adult patients with advanced renal cell carcinoma (RCC) initiating nivolumab for the first time, in real-life conditions in Germany to estimate overall survival (OS) over a 5-year follow-up period The secondary objectives of this study are, among adult patients with advanced RCC initiating nivolumab for the first time, in real-life conditions in Germany: To estimate OS, calculated from the date of initiating treatment with nivolumab, according to the other subgroups of interest To estimate intermediate endpoints, including progression-free survival (PFS); response rates (overall response rate [ORR], best overall response rate [BORR], and best overall response [BOR]; investigator assessed]), duration of response, overall and according to histology types, other subgroups of interest, and treatment characteristics To describe socio-demographic and clinical characteristics of patients overall, and according to histology types, other subgroups of interest, and treatment characteristics To describe management of patients, treatment patterns, and variation in treatment patterns over a 5-year period (ie, dosing, regimen, indication, treatment rationales, treatment duration, and management rationales, and management and characteristics (such as median time to onset, median time to resolution, grade at onset) of treatment-related adverse events [AEs]) overall and according to the Memorial Sloan Kettering Cancer Center (MSKCC) and IMDC score, histology types, and other subgroups of interest To describe the incidence, severity, and management of following types of AEs to estimate toxicity: select AEs (immune-related pneumonitis, immune-related colitis, immune-related hepatitis, immune-related nephritis/renal dysfunction, immune-related endocrinopathies [hyperthyroidism, hypothyroidism, adrenal insufficiency, hypophysitis, diabetes mellitus], and immune-related rash) other immune-related AEs (severe infusion reactions, uveitis, pancreatitis, demyelination, Guillain-Barre Syndrome, myasthenic syndrome, encephalitis, and toxic epidermal necrolysis) other treatment-related AEs To describe patient-reported outcomes and health-related quality of life of patients using the FKSI-19 and EQ 5D questionnaires The exploratory objectives of this study are, among adult patients with advanced RCC initiating nivolumab, in reallife conditions in Germany: To assess the association of the management of select AEs, other immune-related AEs, and other treatmentrelated AEs with OS To examine the association between discontinuing or skipping nivolumab administrations (ie, safety endpoints) and subsequent treatment decisions (ie, describe management of patients and treatment patterns, and variation in treatment patterns, regimen, indication, treatment rationales) To assess the influence of demographic and disease characteristics on the incidence of treatment-related AEs in patients treated with nivolumab To assess the time between completion of the first-line treatment and the start of the treatment with nivolumab as a second-line therapy as well as time on treatment Revised Protocol No.: 01 Date: 20-Sep-2016 6 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab Study Design: This is a German, nationwide, prospective, observational, multicenter study in patients diagnosed with advanced RCC with clear-cell and non-clear-cell histology, who start a new systemic therapy with nivolumab for the first time and within the market authorization approval. Patients are to be enrolled into the study no earlier than the decision to initiate treatment with nivolumab and no later than the first dose of nivolumab treatment. It is mandatory that the treating physician´s decision to start treatment with nivolumab for RCC was taken independently and before the decision to invite the patient to participate in the study. Physicians will be asked to enroll eligible patients consecutively until the maximum inclusion threshold is reached or at the end of a 2-year enrollment inclusion period (whichever occurs first). Patients will be followed for 5 years from index date (ie, treatment initiation) until death, withdrawal of consent, loss of follow-up/record, or to the end of the study, whichever comes first. During the follow-up period, assessment schedules will be performed according to routine local clinical practice. Data entry in the electronic case report form (eCRF) will take place at Day 0, Week 6, Month 3, Month 6, Month 9, Month 12 (Month 18 only questionnaires), Month 24, Month 36, Month 48, and Month 60 (5 years after nivolumab initiation). Study Population: The study will enroll adult patients who are at least 18 years of age at the time of the treatment decision with the diagnosis of advanced RCC (histologically or cytologically confirmed) and whose physician has already decided to initiate a treatment with nivolumab for the first time for the treatment of RCC, according to the label approved in Germany. Patients with a diagnosis of a cancer other than advanced RCC within the past 5 years, ie, a cancer other than RCC that requires systemic or other treatment, will be excluded from enrollment. Data Collection Methods: The study will collect data primarily from oncology care facilities in Germany, both office based and hospital based (community hospitals and university hospitals). Electronic case report forms will be used by study investigators or qualified research staff members to enter data. As part of the routine care, study investigators will evaluate or ask patients about their disease history, treatment history (including nivolumab), and any AE experienced since the previous clinical visit and the related information. The Quality of Life questionnaires FKSI-19 and EQ-5D will be self-administered and completed by the patient. Data Analyses: This study is descriptive in nature and no formal hypotheses will be tested. As this is not a study with pre-specified hypotheses, no comparative analyses assessing the effectiveness of other treatments will be undertaken. Rather, patient and clinical characteristics will be described to provide context for the observed characteristics of patients treated with nivolumab. Patients with a history of another primary malignancy should be analyzed separately. All collected data and endpoint variables will be summarized using descriptive statistics in addition to statistical modeling. Specifically, number of subjects, number of missing observations, mean, 95% confidence interval (CI) for the mean, standard deviation, minimum, median, interquartile range, and maximum, will be provided for continuous variables. For discrete variables, the frequency and percentage by modality, 95% CI, and number of missing observations will be provided. The primary objective of OS will be estimated and plotted using the Kaplan-Meier method for up to 5 years of follow up. Sample Size/Power: In this non-comparative observational study, the sample size was focused on the precision of the estimations, measured as the range of their 95% CIs. Overall survival is the primary endpoint of the study. The sample size was determined to provide an adequate precision to the estimate of OS rate. With a sample size of 323 patients, the precision of the CI for the OS rate would be ± 5.0%, which is considered sufficient to gain relevant conclusions. Limitations/Strengths: As with any observational research, this study is subject to a series of risks of bias. The potential major ones have been explored and taken into account as much as possible in the design and analyses. Revised Protocol No.: 01 Date: 20-Sep-2016 7 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab Limitations The target population (the entire set of individuals to which the findings of the study are to be extrapolated) of this study is the population of patients treated by nivolumab, in the real life setting in Germany, for RCC. A representative sample of the target population will be constituted using multistage sampling, in which physicians from eligible practices and hospitals are to identify and recruit the patients. Sample representativeness may be compromised by selection biases. Moreover the following limitations need to be considered: Hospital representativeness Patient representativeness Information bias Attrition bias Missing data Recall bias Measurement error and misclassification Risk of over-recruitment or under-recruitment In order to minimize the risk for the abovementioned biases, certain measures will be performed. This will, for example, include balancing the site selection according to certain criteria like geography and setting, minimization of the percentage of patients lost-to-follow up by increasing efforts to contact such patients and carrying out of sensitivity analyses. Strengths This is the first collection of real-world data of patients with advanced RCC, who start a new systemic therapy with nivolumab for the first time within the market authorization approval. The safety data and the data regarding management and outcome of treatment-related AEs are expected to meet the high request of information of healthcare providers (HCPs). Generalizability of study results: Patients will be enrolled and treated as per approved label for RCC. The site selection process will ensure that the sites participating are representative in regard to the German landscape of RCC treatment. The study is designed to collect data on a broad segment of patients with RCC and with minimal selection criteria for a high level of external validity. Revised Protocol No.: 01 Date: 20-Sep-2016 8 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab TABLE OF CONTENTS TITLE PAGE ................................................................................................................ SYNOPSIS.................................................................................................................... TABLE OF CONTENTS .............................................................................................. 1 INTRODUCTION ..................................................................................................... 1.1 Study Rationale ................................................................................................. 1.2 Research Questions ........................................................................................... 2 OBJECTIVES ............................................................................................................ 2.1 Primary Objective ............................................................................................. 2.2 Secondary Objectives........................................................................................ 2.3 Exploratory Objectives ..................................................................................... 3 STUDY DESIGN....................................................................................................... 3.1 Overview of Study Design ................................................................................ 3.2 Study Population ............................................................................................... 3.2.1 Inclusion Criteria ..................................................................................... 3.2.2 Exclusion Criteria .................................................................................... 3.3 Data Source/Data Collection Process ............................................................... 3.3.1 Patient Reported Outcome (PRO) Instruments........................................ 3.3.2 Site Information ....................................................................................... 3.3.3 Patient Data ............................................................................................. 3.4 Definitions of Study Variables.......................................................................... 3.4.1 Outcomes/Endpoint Variables ................................................................. 3.4.1.1 Clinical Outcomes ........................................................................... 3.4.1.2 Socio-Demographics and Clinical Characteristics ........................ 3.4.1.3 Treatment Patterns.......................................................................... 3.4.1.4 Incidence, Severity and Management of Adverse Events................ 3.4.1.5 Patient Reported Outcomes ............................................................ 3.4.2 Exposure/Independent Variables of Interest ............................................ 3.4.3 Other Co-variates/Control Variables ...................................................... 4 STATISTICAL ANALYSIS ..................................................................................... 4.1 Statistical Analysis Methods ............................................................................. 4.1.1 Analysis Plan for Primary Objective ....................................................... 4.1.2 Analysis Plan for Secondary Objectives .................................................. 4.1.3 Analysis Plan for Exploratory Objectives................................................ 4.2 Power/Sample Size ........................................................................................... 4.2.1 Physician Sample Size.............................................................................. 5 STUDY LIMITATIONS/STRENGTHS ................................................................... 5.1 Limitations ........................................................................................................ 5.1.1 Threats to Representativeness.................................................................. 5.1.2 Other Study Limitations ........................................................................... 5.1.3 Conclusion on Study Limitations ............................................................. 5.2 Strengths ........................................................................................................... 6 STUDY CONDUCT .................................................................................................. 6.1 Ethics Committee Review and Informed Consent ............................................ 6.1.1 Ethics Committee Review......................................................................... Revised Protocol No.: 01 Date: 20-Sep-2016 1 6 9 11 11 14 15 15 15 16 16 16 18 18 18 19 19 19 19 20 20 20 22 26 27 29 30 31 31 31 32 33 34 34 35 35 36 36 37 38 38 38 39 39 9 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab 6.1.2 Informed Consent ..................................................................................... 6.2 Responsibilities within the Study ..................................................................... 6.2.1 Sponsor Roles and Responsibilities ......................................................... 6.2.2 CRO Roles and Responsibilities .............................................................. 6.2.3 External Advisory/Steering Committee .................................................... 6.3 Confidentiality of Study Data ........................................................................... 6.4 Quality Control ................................................................................................. 6.5 Database Retention and Archiving of Study Documents ................................. 6.6 Registration of Study on Public Website .......................................................... 7 ADVERSE EVENT REPORTING............................................................................ 7.1 Adverse Event Definitions ................................................................................ 7.2 Adverse Event Collection and Reporting ......................................................... 7.2.1 Serious Adverse Event Collection and Reporting .................................... 7.2.2 Non-serious Adverse Event Collection and Reporting ............................ 8 GLOSSARY OF TERMS AND LIST OF ABBREVIATIONS................................ 8.1 Glossary of Terms ............................................................................................. 8.2 List of Abbreviations ........................................................................................ 9 REFERENCES .......................................................................................................... APPENDIX 1 HR QOL QUESTIONNAIRES............................................................. APPENDIX 2 TNM STAGING SYSTEM: TNM CLASSIFICATION FOR RCC .... APPENDIX 3 CTC SEVERITY GRADING ............................................................... 39 39 40 40 40 40 41 41 41 41 41 43 43 44 46 46 46 48 49 53 54 Revised Protocol No.: 01 Date: 20-Sep-2016 10 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab 1 INTRODUCTION 1.1 Study Rationale The European Commission approved nivolumab (OPDIVO) on 25-Feb-2016 for the treatment of advanced renal cell carcinoma (RCC) after prior therapy based on the positive opinion given 1 by the Committee for Medicinal Products for Human Use (CHMP). Nivolumab is also the first and only programmed death-ligand 1 (PD-1) immune checkpoint inhibitor to demonstrate overall survival (OS) benefit in RCC after prior therapy. Approval was based on the results of CheckMate 025. This was a randomized, open-label, phase 3 study of nivolumab in comparison with everolimus. Eligible patients were 18 years of age or older, had histologic confirmation of advanced renal cell carcinoma with a clear-cell component and measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1), and had received one or two previous regimens of antiangiogenic therapy. The stratification was done according to region, Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk group, and the number of previous antiangiogenic therapy regimens (one or two) for advanced renal cell carcinoma. Nivolumab was administered at a dose of 3 mg per kilogram of body weight as a 60-minute intravenous infusion every 2 weeks. Everolimus was administered orally as a daily dose of 10 mg. The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) in the nivolumab group and 19.6 months (95% CI, 17.6 to 23.1) in the everolimus group. The hazard ratio for death (from any cause) with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P = 0.002), which met the prespecified criterion for superiority. The overall survival benefit with nivolumab was observed across prespecified subgroups, including subgroups defined according to region, MSKCC prognostic score, and number of previous regimens of antiangiogenic therapy. The objective response rate was higher with nivolumab than with everolimus (25% vs. 5%; odds ratio 5.98; 95% CI, 3.68 to 9.72; P<0.001). Partial responses were observed in 99 patients (24%) in the nivolumab group and in 20 patients (5%) in the everolimus group. Complete responses were observed in 4 patients (1%) in the nivolumab group and in 2 patients (<1%) in the everolimus group. The median time to response was 3.5 months (range, 1.4 to 24.8) among the 103 patients with a response in the nivolumab group and 3.7 months (range, 1.5 to 11.2) among the 22 patients with a response in the everolimus group; the median duration of response was 12.0 months (range, 0 to 27.6) with nivolumab and 12.0 months (range, 0 to 22.2) with everolimus. The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) in the nivolumab group and 4.4 months (95% CI, 3.7 to 5.5) in the everolimus group (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P = 0.11). Revised Protocol No.: 01 Date: 20-Sep-2016 11 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab Nivolumab demonstrated superior clinical benefit on OS vs everolimus, regardless of PD L1 2 (programmed death ligand-1) expression status. The safety profile of nivolumab is consistent 3,4 with previously reported trials and also favorable compared to everolimus. The clinical patterns of anti-cancer activity observed with nivolumab, as well as the inflammatory adverse reactions that may occur with its use, are thought to be attributed to the immune-based mechanism of action of nivolumab. The adverse events (AEs) related to nivolumab primarily involve the gastrointestinal (GI) tract, skin, liver, endocrine glands, and nervous system, and are generally medically manageable with topical and/or systemic immunosuppressants and omission or permanent discontinuation of nivolumab. Though manageable, theses AEs pose a challenge. The important identified risks associated with nivolumab treatment are immune-related pneumonitis, immune-related colitis, immune-related hepatitis, immune-related nephritis and renal dysfunction, immune-related endocrinopathies, immune-related rash, other immune-related adverse reactions (uveitis, pancreatitis, demyelination, Guillain-Barre Syndrome, myasthenic syndrome, encephalitis, toxic epidermal necrolysis), and severe infusion reactions. The early diagnosis and prompt management of immune-related AEs according to recommended guidelines as specified in the label is important for minimizing the potential for these events to become long lasting or to progress to severe or fatal complications. Among the immune-related AEs, a category of select AEs has been created to group the most common and impactful preferred terms (PTs) by organ category, providing a better estimate of the frequency of similar kinds of organ-related AEs instead of using PTs only. These select AEs are further defined as follows: may differ from or be more severe than AEs caused by non-immunotherapies may require unique (non-standard) intervention such as immunosuppressants (or hormone replacement therapy) early recognition and management may mitigate severe toxicity The PTs included in the select AEs category are those that are expected to be most commonly used to describe pneumonitis, interstitial nephritis, diarrhea/colitis, hepatitis, rash, and endocrinopathies. Hypersensitivity/infusion reactions are also considered a select AE category to facilitate the pooling of the most relevant PTs for analyses of hypersensitivity/infusion reaction events, and not because such events fit the criteria for select AEs listed above. 3 Results of Study CA209010, which enrolled 168 patients, were recently published and a manageable safety profile for nivolumab in metastatic RCC was demonstrated. Patients on study received 1 of 3 possible doses of nivolumab and continued treatment to progression. Median number of doses was 6, 7.5, and 8 for the 0.3-, 2-, and 10-mg/kg dose groups, respectively. A total of 73% (n=122 out of 168) of the patients experienced an AE of some grade; 19 or 11% of those were Grade 3 or 4. Across the 3 treatment groups, the incidence of AEs was similar: 75% (0.3 mg/kg), 67% (2 mg/kg), and 78% (10 mg/kg); Grade 3 and 4 events were highest in the 2-mg/kg group at 17%. Treatment-related AEs of any grade were reported at a frequency of 75% Revised Protocol No.: 01 Date: 20-Sep-2016 12 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab (0.3 mg/kg), 67% (2 mg/kg), and 78% (10 mg/kg) across the 3 groups; Grade 3 or 4 incidence was 5%, 17%, and 13%, respectively. The most common treatment-related AEs across the 3 groups included fatigue, nausea, and pruritus, all of which were highest in the 10-mg/kg group (35%, 13%, and 11%, respectively). In the 10-mg/kg group, an increased incidence of a few events such as rash (13%), diarrhea (15%), dry mouth (11%), and dry skin (15%) was also observed. Hypersensitivity reactions occurred in 2% (0.3- and 2-mg/kg groups) vs 17% in the 10 mg/kg group, but none were higher than Grade 2. Treatment-related AEs lead to discontinuation of study drug for 7% (0.3 mg/kg), 11% (2 mg/kg), and 7% (10 mg/kg) of patients with the most common reason being an elevated level of serum asparate aminotransferase (AST; 2 patients). There were no treatment-related deaths in the study and no high-grade pneumonitis (as were observed in a Phase 1 trial). 4 Study CA209003 enrolled 34 patients with RCC who received doses of nivolumab ranging from 0.1 to 10 mg/kg; dose escalation to 10 mg/kg was achieved without the identification of a maximum tolerated dose. Safety results for the study were reported for the full 296 patients enrolled regardless of tumor type. Overall, any AE regardless of grade or causality was reported by 97% of the patients. Seventy percent (n=207) of the patients experienced a treatment-related AE with 14% (n=41) of those reaching Grade 3 or 4 intensity. The most common treatmentrelated events of at least 10% incidence were fatigue (24%), rash (12%), diarrhea (11%), pruritus (10%), decreased appetite (8%), and nausea (8%). Treatment-related events that occurred in at least 1% of the patients were reported at an incidence of 41%; most common events were pneumonitis (3%), rash (12%), pruritus (9%), vitiligo (3%), and infusion-related reaction (3%); Grade 3/4 events among these patients were of 1% incidence (pneumonitis, diarrhea, AST/ alanine aminotransferase (ALT) increased) or less. Across the treatment groups, the incidence and severity of treatment-related AEs were similar as the dose increased from 0.1 to 10 mg/kg and a similar profile of events was observed across the groups. Fifteen (5%) of the 296 patients on study discontinued treatment due to a treatment-related AE. There were 3 deaths that were deemed treatment-related including 2 patients who died due to pneumonitis and 1 who died due to colorectal cancer. In the CheckMate 025 trial, a Phase 3, randomized and controlled trial of nivolumab vs everolimus, treatment-related AEs of any grade occurred in 319 of the 406 patients (79%) treated with nivolumab (Table 1.1-1). The most common treatment-related AEs were fatigue (134 patients, 33%), nausea (57 patients, 14%), and pruritus (57 patients, 14%). Grade 3 or 4 treatment-related AEs occurred in 76 of the 406 patients (19%); the most common Grade 3 or Grade 4 event was fatigue (10 patients, 2%). Treatment-related AEs leading to treatment discontinuation occurred in 31 of the 406 patients (8%) treated with nivolumab. No deaths from study-drug toxic effects were reported in the nivolumab group. A total of 179 of the 406 patients (44%) who received nivolumab received treatment beyond initial RECIST version 1.1–defined progression because, as assessed by the investigator, they continued to derive clinical benefit from the treatment. Revised Protocol No.: 01 Date: 20-Sep-2016 13 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 Table 1.1-1: CA209653 Nivolumab Treatment-Related Adverse Events Reported in 10% or More of Nivolumab-Treated Patients Nivolumab (N-406), n (%) Events Any Grade Grade 3 or 4 All events 319 (79) 76 (19) Fatigue 134 (33) 10 (2) Nausea 57 (14) 1 (<1) Pruritus 57 (14) 0 Diarrhea 50 (12) 5 (1) Decreased appetite 48 (12) 2 (<) Rash 41 (10) 2 (<) Cough 36 (9) 0 Anemia 32 (8) 7 (2) Dyspnea 39 (7) 3 (1) Peripheral edema 17 (4) 0 Pneumonitis 16 (4) 6 (1) Mucosal inflammation 11 (3) 0 Dysgeusia 11 (3) 0 Hyperglycemia 9 (2) 5 (1) Stomatitis 8 (2) 0 Hypertriglyceridemia 5 (1) 0 Epistaxis 3 (1) 0 Specific safety algorithms have been designed for the select categories of AEs, and are implemented in a unified manner in all current studies in the nivolumab program. These safety algorithms assist the diagnostic, the assessment of relatedness, and the management of the select AEs; also, they are continuously evaluated and adjusted as experience accumulates. The current study will focus on improving precision around the frequency of high-grade select AEs, and on obtaining information on their management outcome. Currently, the treatment experience with nivolumab is based on the experienced gained in clinical trials. Immuno-oncology is an innovative treatment approach and nivolumab is the first approved PD-1 inhibitor for the treatment of RCC. 1.2 Research Questions This study intends to describe the following in patients with advanced RCC initiating nivolumab, over a 5-year follow-up period, in real-life conditions in Germany: Revised Protocol No.: 01 Date: 20-Sep-2016 14 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab What is the effectiveness of nivolumab overall and defined according to histology type (clear-cell and non-clear-cell histology) and various subgroups of interest (demographic and disease characteristics, treatment characteristics)? What is the profile of patients initiating a new systemic therapy with nivolumab for the first time? What is the pattern of use of nivolumab (eg, dosing, regimen, indication, treatment rationales and treatment duration and modification in relation to management of AEs)? What is the safety profile of nivolumab and how are AEs managed? What is the quality of life of patients? 2 OBJECTIVES 2.1 Primary Objective The primary objective of this study is, among adult patients with advanced RCC initiating nivolumab for the first time, in real-life conditions in Germany to estimate OS over a 5-year follow-up period. 2.2 Secondary Objectives The secondary objectives of this study are, among adult patients with advanced RCC initiating nivolumab for the first time, in real-life conditions in Germany: To estimate OS, calculated from the date of initiating treatment with nivolumab, according to the other subgroups of interest To estimate intermediate endpoints, including progression-free survival (PFS); response rates (ORR, BORR, BOR [investigator assessed]); duration of response; overall and according to histology types, other subgroups of interest, and treatment characteristics To describe socio-demographic and clinical characteristics of patients overall and, according to histology types, other subgroups of interest, and treatment characteristics To describe management of patients, treatment patterns, and variation in treatment patterns over a 5-year period (ie, dosing, regimen, indication, treatment rationales, treatment duration, and management and characteristics (such as median time to onset, median time to resolution, grade at onset) of treatment-related AEs) overall and according to MSKCC and IMDC score, histology types, and other subgroups of interest To describe the incidence, severity, and management of the following types of AEs to estimate toxicity: select AEs (immune-related pneumonitis, immune-related colitis, immune-related hepatitis, immune-related nephritis/renal dysfunction, immune-related endocrinopathies [hyperthyroidism, hypothyroidism, adrenal insufficiency, hypophysitis, diabetes mellitus], and immune-related rash) other immune-related AEs (severe infusion reactions, uveitis, pancreatitis, demyelination, Guillain-Barre Syndrome, myasthenic syndrome, encephalitis, toxic epidermal necrolysis) other treatment-related AEs Revised Protocol No.: 01 Date: 20-Sep-2016 15 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 2.3 CA209653 Nivolumab To describe patient-reported outcomes and health-related quality of life of patients using the FKSI-19 and EQ-5D questionnaires Exploratory Objectives To assess the association of the management of select AEs, other immune-related AEs, and other treatment-related AEs with OS To examine the association between discontinuing or skipping nivolumab administrations (safety endpoints) and subsequent treatment decisions (ie, describe management of patients and treatment patterns, and variation in treatment patterns, regimen, indication, treatment rationales) To assess the influence of demographic and disease characteristics on the incidence of treatment-related AEs in patients treated with nivolumab To assess the time between completion of the first-line treatment and the start of the treatment with nivolumab as a second-line therapy as well as time on treatment 3 STUDY DESIGN 3.1 Overview of Study Design This is a German, nationwide, prospective, observational, multicenter study in patients diagnosed with advanced RCC, who start a new systemic therapy with nivolumab for the first time and within the market authorization approval according to the label approved in Germany. Patients are to be enrolled into the study no earlier than the decision to initiate treatment with nivolumab and no later than the first dose of nivolumab treatment. It is mandatory that the treating physician´s decision to start treatment with nivolumab for RCC was taken independently and before the decision to invite the patient to participate in the study. Index date (Day 0) corresponds to the day of nivolumab initiation (administration of the first dose of treatment). According to usual practice in Germany, decision to prescribe nivolumab is taken by the medical team, after the patient visit when clinical evaluation is done. During the next patient visit, the therapeutic decision is confirmed with the patient and the administration of nivolumab is planned. If the patient meets the selection criteria, the investigator should then invite the patient to participate in the study and collect his/her consent to participate. Enrollment in the study is then clearly distinguished from the therapeutic decision to initiate nivolumab. Physicians will be asked to enroll eligible patients consecutively until the maximum inclusion threshold is reached or at the end of a 2-year enrollment inclusion period (whichever occurs first). Patients will be followed for 5 years from D0 until death, withdrawal of consent, loss of follow-up/record, or to end of study, whichever comes first. Patients will be censored at death, last record or assessment for those lost to follow up, or date of enrollment into a clinical trial (if known). As this is a non-interventional study, no visits or measurements will be made mandatory by the protocol and data collection at these pre-specified time-points will only take place if the patient visits the site. During the follow-up period, assessment schedules will be performed according to routine local clinical practice. Data entry in the electronic case report form (eCRF) will take place at Day 0, Week 6, Month 3, Month 6, Month 9, Month 12 (Month 18 only questionnaires), Revised Protocol No.: 01 Date: 20-Sep-2016 16 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab Month 24, Month 36, Month 48, and Month 60 (5 years after nivolumab initiation). Investigators will be instructed to collect data from the visit nearest to the time point. Adverse events will be collected according to guidelines and timelines in Section 7. Patients will be asked to provide quality of life data at regular intervals throughout the study follow-up. The validated FKSI-19 and EQ-5D that will be used are considered a formalization of the usual interviews done by the physician and therefore are not a change from usual practice. Sites will receive fees to compensate for the time spent for data collection and entry into eCRFs (abstraction tool). Since the study is intended to reflect usual clinical practice, physicians will not be required to perform any mandatory patient assessments or laboratory tests that they would not ordinarily do in treating their patients. This protocol requires that sites submit all relevant documentation to their respective institutional review board (IRB) or Ethics Committee (EC) and obtain either approval or acknowledgment of notification, depending on the local requirements. Participating patients must provide written informed consent and have the right to withdraw from the study at any time. This study will be conducted with support of a clinical research organization (CRO). A Scientific Advisory Council will be formed taking into consideration participating physicians and centers to provide scientific and clinical input on protocol design, study scientific execution, and data analysis. The suggested study design is illustrated in Figure 3.1-1. Figure 3.1-1: Study Design NOTE: At site level. Abbreviations: D = Day; M = month; W = week. Sampling Frame A 2-stage clustered sampling process will be applied, combining random sampling for physicians and systematic sampling method for patients. It is assumed that a representative sample of physicians is necessary to obtain a representative sample of patients in the cohort. Revised Protocol No.: 01 Date: 20-Sep-2016 17 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab Stage 1: Site Selection Eligible patients will be selected from approximately 48 sites in Germany. Effort will be made to recruit sites with representative medical practices and to provide epidemiological data describing the many real-life aspects of RCC treatment and its burden on the healthcare system. An initial comprehensive site sampling database will be established incorporating inputs from premarketing clinical studies and external advisors to obtain a list that is as comprehensive as possible of practices and hospitals caring for patients with RCC in Germany. The site sampling method will take into consideration certain criteria, including the number of cared RCC patients, physician profiles, healthcare environments (eg, rural, urban, suburban), and medical practices (eg, office based, hospital based, and academic setting). The site sampling method will take into consideration stratification criteria, including the number of RCC patients receiving care, physician profiles, healthcare environments (eg, rural, urban, suburban), medical practices (eg, office based, hospital based, academic setting). Stratifications will aim at ensuring representativeness compared to the initial sampling database. Invitation letters will be sent to all sites from the sample. Assuming approximately 60% rate of sites agree to participate in the study, it is estimated that approximately 80 sites will be contacted. Obtained responses, either positive or negative, will be tracked and recorded. In case response rates are lower than expected, non-responders will be called by phone in the order of the random sampling until the target number is achieved. In case the targeted number of active participants cannot be reached, depending on the progress of the study, either site sample will be extended (new sampling applied to the sampling database) and/or the maximum number of patients per site will be extended and/or the enrollment period will be prolonged. Stage 2: Patient Selection Patient selection will be based on systematic sampling technique, ie, all consecutive eligible patients are expected to be included in the study. 3.2 Study Population 3.2.1 Inclusion Criteria Patients fulfilling the following criteria will be enrolled: Adult patients (At least 18 years of age at time of treatment decision) diagnosis of advanced RCC diagnosis of RCC has been confirmed by histology or cytology treatment decision to initiate a treatment with nivolumab for the first time for the treatment of RCC (according to the label approved in Germany) has already been taken Patients who provided informed consent to participate in the study 3.2.2 Exclusion Criteria Patients fulfilling the following criteria will be not be enrolled in any component of the study: Revised Protocol No.: 01 Date: 20-Sep-2016 18 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab Patients with a diagnosis of a cancer other than advanced RCC within the past 5 years, ie, a cancer other than RCC that requires systemic or other treatment. Patients that have been treated curatively more than 5 years ago with no evidence of recurrence and prostate cancer patients in active surveillance can be included. Patients previously treated with nivolumab and/or ipilimumab. Patients currently included in an interventional clinical trial for their advanced RCC. Patients who have completed their participation in an interventional trial; or who are not receiving study drug anymore and who are only followed-up for OS can be enrolled. 3.3 Data Source/Data Collection Process 3.3.1 Patient Reported Outcome (PRO) Instruments Patient Reported Outcomes (PRO) will be collected in the context of this study at each visit, over the 5-year follow-up period, using the validated FKSI-19 and EQ-5D. These scales will formalize the usual interviews done by the physicians and allow assessment of patient quality of life. Data will be collected on paper-based questionnaires and will be self-administered by the patient. 3.3.2 Site Information All eligible physicians will be contacted by mail/letter. A letter signed by both BMS and the Scientific Committee, a confidentiality agreement, and a reply form will be sent to each physician to ask for their agreement to participate in the study as an investigator. Physicians refusing to participate will be asked to send the completed reply form. No queries will be issued for reply forms and data will be considered as they are. Telephone follow-ups are planned for physicians that did not return the reply form. All site/physicians characteristics will be transferred to a database to allow assessment of representativeness of participating physicians. 3.3.3 Patient Data The study will collect data primarily from oncology care facilities in Germany, both office based and hospital based. Electronic case report forms will be used by study investigators or qualified research staff members to enter data. As part of the routine care, study investigators will evaluate or ask patients about their disease history, treatment history, and any AE experienced since the previous clinical visit and the related information. The Quality of Life questionnaires FKSI-19 and EQ-5D will be completed by the patient. If a serious adverse event (SAE) was treated outside of the study sites, the information about the SAE, management, and outcomes will be obtained by study investigators or site study staff from the healthcare facilities, where the patients’ SAEs were treated and managed. As this is a non-interventional study, mandatory assessments will not be required from the study sites or patients. However, data collection/reporting will be conducted in a consistent way among different cohorts whenever possible to avoid bias in the data collection process. Data will be entered by all sites onto eCRFs, with monitoring for source data verification. Data will be collected from eCRFs, which are to be completed by site staff. Patients will report quality of life via paper-based validated questionnaires. Revised Protocol No.: 01 Date: 20-Sep-2016 19 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab Physicians will be asked to report both serious and non-serious AEs for all patients, regardless if treatment-related (adverse reactions) or not, and regardless of severity (mild, moderate, severe, or life-threatening), as defined per reporting guidelines in Section 7). Physicians will also be asked to report what action was taken to manage these adverse reactions. Safety data will be collected on eCRFs on an ongoing basis throughout study follow-up. Data entry is expected during the first year at baseline, Week 6, and Months 3, 6, 9, and 12, thereafter every year, independently of the actual office visit frequency; data assessments will include independent variables, dependent variables, and other co-variates (see Section 3.4.3). In addition, on Month 18, only data of questionnaires will be entered. Prior to interim and database locks, all data must be entered within a week of the visit date. Data will be collected for each patient for 5 years from the study Day 0 (ie, initiation of therapy). Enrollment of the 323 patients is expected to occur over 2 years at site level and patients will be followed for 5 years. Patient database characteristics will be described in a Data Validation Plan (DVP) approved prior to putting electronic CRFs into production for sites to start collecting data. Edit checks, described in the Data Management Plan (DMP), and tested prior to starting data entry process, will be defined to ensure validity of the database with a focus on missing, implausible, or inconsistent data. All therapies (ie, concomitant/prior treatments; or anti-cancer medication that will be administered in later treatment lines) documented will be coded using the World Health Organization (WHO) Drug Dictionary. Medical history, any diseases and AEs will be coded using the latest Medical Dictionary for Regulatory Activities (MedDRA) version. Re-coding of already coded terms will only be done for interim analysis (if deemed necessary) and for final analysis. Prior to locking the final database, patient data listings for key variables and final checks will be run to identify remaining, missing, or inconsistent information contained in the database and to define analysis populations. These listings and tables will be reviewed during a final data review process by the study team and scientific committee, and a data review report will be prepared, stating all decisions taken. The database will then be locked and transferred to statisticians for analysis. The statistical analysis plan (SAP) will be prepared and approved prior to database lock. 3.4 Definitions of Study Variables 3.4.1 Outcomes/Endpoint Variables 3.4.1.1 Clinical Outcomes Part of the objectives is to describe the clinical outcomes (Table 3.4.1.1-1). Table 3.4.1.1-1: Subsection Overall Survival Clinical Outcomes Variables Overall survival (OS) (Time to event) Definition Time since index date (initial diagnosis and treatment with nivolumab) until date of death due to any cause Revised Protocol No.: 01 Date: 20-Sep-2016 Timing Collected a continuously 20 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 Table 3.4.1.1-1: Subsection CA209653 Nivolumab Clinical Outcomes Variables Definition Timing OS will be censored on the last date a subject was known to be alive For patients that are lost to follow up, who enroll into a clinical trial or die, data will be censored at that point, but all previous records retained to allow analysis of person time. Component variables needed: Cause of Death (Where available) Intermediate endpoints Death (ICD-10 cause of death coded) Date of death All-cause mortality Cause-specific Death due to treatment Progression (investigator assessed and per RECIST, if available) Progression-Free Survival (PFS) Time to progression Continuous If recorded At each available tumor assessment which is collected either at ‘first assessment after initial treatment’ or during follow-up: Investigator assessed: Disease progression = Yes, if best therapy tumor response = disease progression Disease progression = No, if best therapy tumor response = complete/ near complete response, tumor shrinkage or mixed response Per RECIST: Disease progression = Yes, if best therapy tumor response = PD Disease progression = No, if best therapy tumor response=CR, PR, or SD Time since index date (initial diagnosis and treatment with nivolumab) to either the first disease progression date (investigator assessed or per RECIST if available) or last known tumor assessment date, or death due to any cause, whichever occurs first Time since index date until progression (investigator assessed or per RECIST if available) Tumor response Overall tumor response will be assessed by investigator and if available per RECIST criteria as well as Best overall response rate (BORR) disease control rate (DCR) Continuous Continuous Continuous Continuous Revised Protocol No.: 01 Date: 20-Sep-2016 a a a a a 21 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 Table 3.4.1.1-1: Subsection CA209653 Nivolumab Clinical Outcomes Variables Best Overall Response per RECIST Investigator assessed Best Overall Response Rate (BORR) Disease Control Rate (DCR) Definition Timing The highest level of response among all available best therapy responses in tumor assessment during follow-up assessed by RECIST. CR is the highest and PD is the lowest. The highest level of response among all available best therapy responses in tumor assessment during follow-up assessed by the investigator. Complete/near complete response is the highest and disease progression is the lowest. Total number of patients whose BOR = CR or PR, divided by total number of patients Continuous, if RECIST available Total number of patients whose BOR = CR, PR, or SD, divided by total number of patients Continuous, if RECIST available a Continuous a a Continuous, if RECIST available a Duration of response Time from response to progression Remission status Relapse Best response to first-line treatment Death due to treatment Abbreviations: BORR = best overall response rate; CR = complete response; DCR = disease control rate; ICD-10 = International Statistical Classification of Disease and Related Health Problems (version 9, 10); irRc = immune-related response criteria; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PR = partial response; SD = stable disease. a Data will be collected at visits Week 6 and Months 3, 6, 9, 12, 24, 36, 48, and 60. 3.4.1.2 Socio-Demographics and Clinical Characteristics Baseline characteristics such as disease history or treatment history will be assessed before the date and time of the first dose of nivolumab treatment. Karnofsky Performance Status is the performance status within 2 weeks prior to the first dose of nivolumab treatment. In cases where the time (onset time of event or evaluation time and dosing time) is missing or not collected, the following definitions will apply: Pre-treatment diseases/conditions will be defined as diseases/conditions with an onset date prior to but not including the day of the first dose of study treatment. Baseline measurements (laboratory tests, pulse oximetry, and vital signs) are defined as measurements with a date on or prior to the day of the first dose of study treatment. If there are multiple valid assessments, the assessment closest to the day (and time, if collected) of the first dose of nivolumab treatment will be used as the baseline measurements. If multiple assessments are collected on the same date (and time, if collected), the assessment with the latest database entry date (and time, if collected) will be considered as baseline. Revised Protocol No.: 01 Date: 20-Sep-2016 22 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab The socio-demographics and clinical characteristics described in Table 3.4.1.2-1 are to be considered. Data necessary to derive these endpoints will be collected if available. Table 3.4.1.2-1: Socio-Demographics and Clinical Characteristics Subsection Variables Definition Timing Initial Diagnosis of RCC Disease stage at initial diagnosis Staging of RCC Baseline [Age at diagnosis ( 65 years/ > 65 years)] Date of birth - First date of primary diagnosis Disease stage at initial diagnosis and enrollment Diagnosis Histology Location Date of first systemic treatment Status post nephrectomy Need for dialysis before enrollment Staging / subtypes Overall cancer stage (III or IV) See Appendix 2 Hemoglobin level Baseline and all visits, if available Baseline and all visits, if available WBC Absolute neutrophil count Lymphocyte count GGT Aspartate aminotransferase Alanine aminotransferase Platelet count Sodium Potassium LDH Alkaline phosphatase Serum albumin level Serum creatinine Creatinine clearance (GFR) Blood urea nitrogen Calcium Medical imaging test CT/MRI Ultrasound Revised Protocol No.: 01 Date: 20-Sep-2016 23 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 Table 3.4.1.2-1: Subsection CA209653 Nivolumab Socio-Demographics and Clinical Characteristics Variables Definition Timing Conventional x-ray Bone scintigraphy X-Ray Resectable/unresectable Overall cancer stage of population (TNM) Metastatic stage [TNM status at diagnosis] Size of tumor Number of disease sites Number of metastatic sites at treatment initiation Site(s) of tumor (0 vs 1 vs 2 vs 3–6 vs > 6) Localization of metastases at treatment initiation & follow up (liver vs lung vs bone vs brain vs adrenal vs leptomeningeal carcinomatosis vs malignant ascites vs peritoneal other) Malignant pleural effusion Malignant ascites Histological subtypes RCC Clear-cell RCC, papillary RCC (Typ 1/2), chromophobe RCC, other, sarcomatoid parts present Baseline Performance status Karnofsky score 100 - Normal; no complaints; no evidence of disease. 90 - Able to carry on normal activity; minor signs or symptoms of disease. 80 - Normal activity with effort; some signs or symptoms of disease. 70 - Cares for self; unable to carry on normal activity or to do active work. 60 - Requires occasional assistance, but is able to care for most of their personal needs. 50 - Requires considerable assistance and frequent medical care. 40 - Disabled; requires special care and assistance. 30 - Severely disabled; hospital Baseline and all Revised Protocol No.: 01 Date: 20-Sep-2016 a visits 24 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 Table 3.4.1.2-1: Subsection CA209653 Nivolumab Socio-Demographics and Clinical Characteristics Variables Definition Timing admission is indicated although death not imminent. 20 - Very sick; hospital admission necessary; active supportive treatment necessary. 10 - Moribund; fatal processes progressing rapidly. 0 - Dead Co morbidities Patient demographics MSKCC score Baseline IMDC score Baseline Autoimmune diseases Liver disorders Disorder of gastrointestinal / urogenital tract Disorders of cardio-vascular system CNS disorders Pulmonary disorders Malignant disorders Metabolic diseases Others Gender Baseline and if any new comorbidities occurred Male - female a Baseline Age Height Weight All visits a BMI History of cancer History of other primary malignancies and specification of the malignancy Possible family history of renal cancer History of smoking Baseline Previous enrollment in an Date of enrollment; details of Baseline interventional study (RCTS) RCT and treatment Abbreviations: BMI = body mass index; CT = computed tomography; GFR = glomerular filtration rate; GGT = gamma-glutamyl transferase; IMDC = International Metastatic Renal Cell Carcinoma Database Consortium; LDH = lactate dehydrogenase; MSKCC = Memorial Sloan Kettering Cancer Center; MRI = magnetic resonance imaging; RCC = renal cell carcinoma; RCT = randomized controlled trial; TNM = tumor node metastasis; WBC = white blood cell count. RCT enrollment a Data will be entered at visits Day 0, Week 6, and Months 3, 6, 9, 12, 24, 36, 48, and 60. Revised Protocol No.: 01 Date: 20-Sep-2016 25 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 3.4.1.3 CA209653 Nivolumab Treatment Patterns The endpoints to assess management of patients and treatment patterns and their evolution along the follow-up period are described in Table 3.4.1.3-1, Table 3.4.1.3-2, and Table 3.4.1.3-3. Data necessary to derive these endpoints will be collected if available. Table 3.4.1.3-1: Subsection Type of treatment previously received RCC Treatment History (Baseline: Therapies before Index Date) Variables Definitions Timing Stage of RCC , which was treated Line of treatment Radiotherapy (abdomen) Radiotherapy (other region) Chemotherapy Targeted therapy Systemic treatment Surgery for cancer (date/type) Baseline Concomitant medications Abbreviation: RCC = renal cell carcinoma. Table 3.4.1.3-2: Nivolumab Treatment Characteristics (at Initiation - Index Date) Sub-section Nivolumab treatment Variables Definition Timing Stage of RCC Stage III or Stage IV Baseline Line of treatment Dosing Date of first infusion Abbreviation: RCC = renal cell carcinoma. Table 3.4.1.3-3: Details on Prior and Evolution of Current Treatment Patterns (at and after Study Entry Index Date, during Study Period) Sub-section Treatment stage Variables Definitions Treatment stage Timing All a visits Line of treatment Type of therapy Radiotherapy details Chemotherapy details Systemic treatment Surgical treatment Pre-existing medications Systemic treatment details Drug therapy details Drug name: ATC codes Dosage Dose (mg/day) Number of received administrations Revised Protocol No.: 01 Date: 20-Sep-2016 26 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 Table 3.4.1.3-3: CA209653 Nivolumab Details on Prior and Evolution of Current Treatment Patterns (at and after Study Entry Index Date, during Study Period) Sub-section Variables Definitions Start date; end date Timing Length of treatment Concomitant medication Completion/discontinuation of nivolumab Permanent discontinuation of nivolumab Temporary discontinuation Reason for discontinuation Time-to-Treatment Discontinuation Treatment after progression Permanent discontinuation is defined as no infusion 6 weeks or less after the last infusion (3 missed infusions). Temporary discontinuation is defined as 1 or 2 skipped infusions. If nivolumab is restarted after 3 skipped infusions it should be considered as part of a new treatment cycle. Reasons: death, disease progression, study drug related toxicity, non-study drug related toxicity, patient request, pregnancy, lost to follow-up, other Time from date of nivolumab treatment initiation to date of last infusion + 2 weeks (this will be the first ‘missed’ infusion), or the date of failure from a competing risk (eg, death). Yes / No/ Length of treatment after progression All a visits Procedures to manage treatmentrelated AEs Abbreviations: AEs = adverse events; ATC = Anatomical Therapeutic Chemical (ATC) Classification System. a Data will be collected at visits Day 0, Week 6, and Months 3, 6, 9, 12, 24, 36, 48, and 60. 3.4.1.4 Incidence, Severity and Management of Adverse Events The endpoints to assess frequency, severity, and management of treatment-related AEs, select AEs, and other immune-related AEs are described in this section and in the following tables. Data necessary to derive these endpoints will be collected if available. Adverse event collection and reporting will follow the guidelines outlined in Section 7.2. Adverse Events An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally Revised Protocol No.: 01 Date: 20-Sep-2016 27 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab associated with the use of a medicinal product, whether or not considered related to the medicinal product. The event severity for all AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Grading System, Version 4.0. For details, please refer to Appendix 3. Treatment-Related Adverse Events Treatment-related AEs are those events with a relationship to study drug recorded as “Related” on the CRF. Treatment-related AEs as reported by study investigators will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), using the most recent version of the dictionary at the time of the database lock for final analysis (and interim analysis, if deemed necessary). Select Adverse Events Among the immune-related AEs, a category of “select AEs” has been created to group the most common and impactful preferred terms (PTs) by organ category, providing a better estimate of the frequency of similar kinds of organ-related AEs instead of using PTs only. These select AEs are further defined as follows: may differ from or be more severe than AEs caused by non-immuno-therapies may require unique (non-standard) intervention such as immuno-suppressants (or hormone replacement therapy), and early recognition and management may mitigate severe toxicity. The PTs included in the ‘select AEs’ category (Table 3.4.1.4-1) are those that are expected to be most commonly used to describe: Pneumonitis Interstitial nephritis Diarrhea/colitis Hepatitis Rash Endocrinopathies Other Immune-Related AEs In this study, immune-related AEs are defined as nivolumab treatment-related AEs that are consistent with the immune-based mechanisms of action of nivolumab, per investigator-assessed causality, and can occur during or after nivolumab treatment. Select AEs are special group of AEs, which follow the criteria listed above. Immune-related AEs which are not catagorized as select AEs are considered as other immune-related AEs. Other immune-related AEs might be: Severe infusion reactions Uveitis Revised Protocol No.: 01 Date: 20-Sep-2016 28 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab Pancreatitis Demyelination Guillain-Barre Syndrome Myasthenic syndrome Encephalitis Toxic epidermal necrolysis Table 3.4.1.4-1: Adverse Events (Safety Data and Toxicity) Subsection AEs, Treatment Related AEs, Select AEs, Other Immunerelated AEs Variables Incidence rate AE Characteristics Severity Management Definition Number of new cases per population at risk over the follow-up period (nb per person-time) Note: this will be based on the first occurrence of event during the follow-up period Characteristics, such as median time to onset, median time to resolution, grade at onset Toxicity: Hematological and nonhematological toxicities by grade using NCI CTCAE version 4.0 Timing Continuous Procedures to manage treatment-related adverse events Abbreviations: AEs = adverse events; CTCAE = Common Terminology Criteria for Adverse Events; NCI CTC = National Cancer Institute Common Toxicity Criteria. 3.4.1.5 Patient Reported Outcomes The endpoints to assess patient reported outcomes are described in this section and in the following tables. Data necessary to derive these endpoints will be collected if available. To assess patient benefit and quality of life (QoL), patients should be asked to complete PRO (patient reported outcomes) questionnaires at baseline and at the visits as indicated in Table 3.4.1.5-1 The PRO questionnaires recommended are described in Table 3.4.1.5-1 and include the following: Utility: European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Quality of Life: FKSI-19 Questionnaire (Functional Assessment of Cancer Therapy –Kidney Symptom Index) Table 3.4.1.5-1: Sub section Health-Related Quality of Life (HRQoL) Measures Variables Definition Revised Protocol No.: 01 Date: 20-Sep-2016 Timing 29 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 PRO CA209653 Nivolumab Utility: EQ-5D Questionnaire The EQ-5D descriptive system consists of 5 dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression, each with 3 levels (eg, no problems, moderate problems, extreme problems) Baseline, Week 6, and Months 3, 6, 9, 12, 18, 24, 36, 48, and 60 FKSI-19 The 19 items of the FKSI-19 will be graded by the patient on a scale from 0 to 4 (range “not at all to very much”). Baseline, Week 6, and Months 3, 6, 9, 12, 18, 24, 36, 48, and 60 Abbreviations: EQ-5D = European Quality of Life-5 Dimensions; HRQoL = Health-Related Quality of Life; FKSI = Functional Assessment of Cancer Therapy –Kidney Symptom Index; VAS = Visual Acuity Scale. 3.4.2 Exposure/Independent Variables of Interest Exposure will be described including, but not limited to: Percentage of patients receiving bi-weekly nivolumab Percentage of patients receiving nivolumab as second- or third-line therapy Median treatment duration and range by line and histology Rate of permanent and temporary discontinuations Reasons for discontinuation of nivolumab Part of the objectives is to describe endpoints according to different subgroups of patients. These subgroups of interest, include, but are not limited to: Patient and clinical characteristics: Age > 65 years Line of therapy > 2 Karnofsky PS 70 Testing flow: fact of testing/ retesting for biomarkers, results Patients with brain metastases Patients with leptomeningeal carcinomatosis Patients with a history of another primary malignancy separately Patients with known auto-immune disease Patients with known hepatitis Patients with favorable, intermediate and poor prognosis (as per MSKCC and IMDC risk groups) Treatment characteristics Patients with status post radical nephrectomy Patients with prior palliative radiotherapy (≤2 weeks prior to first dose of nivolumab) Patients with prior radiotherapy to primary tumor or brain or other sites of metastases or of the abdomen (≤2 weeks prior to first dose of nivolumab) Revised Protocol No.: 01 Date: 20-Sep-2016 30 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 3.4.3 CA209653 Nivolumab Other Co-variates/Control Variables Variables used to assess the representativeness of the sample are listed in Table 3.4.3-1. Table 3.4.3-1: Variables Used to Assess Sample Representativeness Variable Sample Representativeness Type of institution Office-based/community hospital-based/university hospital-based Specialization of the treating physician Oncologist and/ or urologist Hospital activity Number of patients with renal cancer and chemotherapy in 2014, as evaluated during feasibility assessment Hospital location Geographical region 4 STATISTICAL ANALYSIS This section presents an overview of the statistical analysis planned. In addition to the final analysis (at the end of follow-up, describing 5-year outcomes), interim analyses are planned: At the end of inclusion period, using Day 0 data, to describe the baseline characteristics of patients initiating nivolumab After each year of follow-up, to describe 1-, 2-, 3-, 4-, and 5-year outcomes Details will be presented in a SAP to be prepared subsequently. 4.1 Statistical Analysis Methods This study is descriptive in nature and no formal hypotheses will be tested. As this is not a study with pre-specified hypotheses, no comparative analyses assessing the effectiveness of other treatments will be undertaken. Rather, patient and clinical characteristics will be described for all treatment cohorts to provide context for the observed characteristics of patients treated with nivolumab. Patients with a history of another primary malignancy should be analyzed separately. The first step in the evaluation of the data will be to use standard exploratory and descriptive analyses to gain an understanding of the qualitative and quantitative nature of the data collected and of the characteristics of the sample studied. Data validation and data cleansing to ensure data quality will be performed. The statistical analysis will be performed using SAS for statistical computing software (additional details are provided in the SAP). Results will be displayed using tables, listings, and/or graphs. All collected data and endpoint variables will be summarized using descriptive statistics in addition to statistical modeling. Specifically, number of subjects, number of missing observations, mean, 95% CI for the mean, standard deviation, minimum, median, interquartile range, and maximum, will be provided for continuous variables. For discrete variables, the frequency and percentage by modality, 95% CI, and number of missing observations will be provided. Revised Protocol No.: 01 Date: 20-Sep-2016 31 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab All patients who fulfill the study entry criteria will be included in the data set for analyses. Within a study, data will be collected at different levels and some clustering and hierarchies will be intrinsic to the data collected going from the bottom level data at patient level through time, to higher levels at clinic/community levels. Within each level in this hierarchy, there will be heterogeneity that could be explained (or controlled) by certain characteristics (at patient, clinic, country level) and some that might be just random. Therefore, multi-level hierarchical Bayesian models may be used to account for the nested nature of the data. Within the hierarchical model setting, fixed effect models, random effect models along with mixed effects models may also be explored. Random effects allow the model to incorporate possible extra variation due to unknown sources of uncertainty, making a model somewhat more realistic in certain situations. For exploratory objectives, regression techniques will be used to evaluate and prune models back to identify significant effects using a backwards selection procedure. Model goodness of fit will be assessed using common measures such as the Akaike’s information criterion (AIC), the Schwarz Bayesian information criterion (BIC), and the deviance information criterion (DIC). Missing Data Special attention will be paid to the handling of missing data and the missing data mechanisms. On top of common sources of missing data, such as drop-outs, the missing data patterns in observational studies might show various not-ignorable (missing-not-at-random) distributions. Data missing not at random (MNAR) could potentially be a strong biasing influence. When missing data occur from an MNAR process, appropriate analysis requires the joint modeling of the outcome along with the missing data mechanism. Assumptions about the missing values mechanism will be stated and used to inform a well-defined statistical model with complete data, which may be developed using a multiple-imputation process. The possible incorporation of incomplete data into the model will be explored in situations where it is acceptable to assume that the missing value mechanism can be ignored (MCAR – missing completely at random). This can jointly be handled in the Bayesian approach as it treats missing data as additional unknown quantities for which a posterior distribution can be estimated. Sensitivity Analyses Sensitivity analyses will be conducted to evaluate the impact of the missing data mechanisms as well as to check sensitivity to the assumptions in the regression methods and the hierarchical setting (exploratory objectives). Estimates obtained from the models will be examined with unadjusted estimates to assess consistency of effect estimates, and assess for outlier effects. 4.1.1 Analysis Plan for Primary Objective Overall survival (OS) will be estimated and plotted using the Kaplan-Meier method for up to 5 years of follow-up. The mean/median OS, with the corresponding two-sided 95% CIs, will be reported Revised Protocol No.: 01 Date: 20-Sep-2016 32 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab The proportion of patients surviving to specific timepoints (1, 2, 3, 4, and 5 years) will be estimated and reported along with the corresponding 2-sided 95% CIs OS will be estimated for patients treated with nivolumab, and for the subgroups detailed in Section 3.4.2. Univariate Analyses Median survival and corresponding 95% CIs, overall and for each of the subgroups will be calculated Hazard ratios (HRs) and corresponding 2-sided 95% CIs may be estimated with Hierarchical Bayesian Survival Analysis/Cox proportional hazards models to explore the association of each subgroup (eg, gender) with overall survival 4.1.2 Analysis Plan for Secondary Objectives The analysis of PFS will be similar to the OS. In particular, PFS will be estimated using the Kaplan-Meier method. The median/mean PFS and the corresponding 2-sided 95% CIs will be estimated. The proportion of patients with first disease progression or death from any cause, whichever occurs first, will be estimated at 1, 2, 3, 4, and 5 years and the corresponding 2-sided 95% CIs will be reported. Also, the association of various patient or disease characteristics with PFS will be assessed following a similar procedure as OS. Overall response rate and BORR will be summarized including main descriptive statistics: mean / median estimates and confidence intervals will be provided. Patient and disease characteristics at the start of nivolumab treatment will be summarized using descriptive statistics; subgroups of patients who might be presenting different effects to the treatments will be explored and identified. Management of patients, treatment patterns, and variations in treatment patterns in adult patients diagnosed with advanced RCC will be assessed. Treatment patterns in the data will be evaluated using frequency tables, and main descriptive statistics (central estimates and confidence intervals) that will help us recognize the main (long term) observed treatment pattern. All treatment-related AEs will be coded by severity grade. Descriptive statistics will be used to describe the incidence and severity of select adverse events, other immune-related AEs and other treatment-related AEs and toxicities. The incidence will be calculated as the number of patients with AEs divided by total patients. Adverse events by subgroup will be described, although it is expected that the analysis will be limited by small numbers expected. Quality of life outcomes will be summarized and compared for the prospective patients regarding the following points: Mean change from baseline to assessment points throughout the study will be evaluated At each time point for analysis, the number of patients who completed the questionnaires will be reported as a percentage of eligible patients Data are to be entered at baseline, Week 6, thereafter every 3 months (counted relative to treatment initiation) during the first year of enrollment, thereafter every year. Questionnaires Revised Protocol No.: 01 Date: 20-Sep-2016 33 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab will in addition be collected after 18 months of treatment. Every 6 months in the second year, and once per year thereafter 4.1.3 Analysis Plan for Exploratory Objectives To assess the association of the management of select AEs, other immune-related AEs, and other treatment-related AEs with OS To examine the association between discontinuing/or skipping nivolumab administrations (safety endpoints) and subsequent treatment decisions (ie, describe management of patients and treatment patterns, and variation in treatment patterns, regimen, indication, treatment rationales) after discontinuing/or skipping nivolumab. To assess the influence of clinical/ demographical characteristics on the incidence of treatment related AEs in patients treated with nivolumab To assess the time between completion of the first-line treatment and the start of the treatment with nivolumab as a second-line therapy as well as time on treatment Multi-level hierarchical mixed effects regression models may be used to explore these relationships. When the outcome is time-to-event or survival, multivariable survival models or Cox proportional hazard models will be used to calculate the hazard ratios (HRs) with their 95% CIs to estimate the strength of the association and precision. Stepwise procedures will be used to assess the significance of each of the variables to explain differences and heterogeneity in the data. When the outcomes imply counts or proportions, Generalized Mixed Models will be used taking into account Poisson or Binomial transformations, respectively, to account for the scales. The same stepwise procedure will be followed to assess the significance of explanatory variables. Although this study is not comparative, treatment allocation decisions and management and its joint relationship with patient characteristics and clinical outcomes is of particular importance to identify potential confounders. 4.2 Power/Sample Size In this non-comparative observational study, the sample size was focused on the precision of the estimations, measured as the range of their 95% confidence intervals. Overall survival is the primary endpoint of the study. The sample size was determined to provide an adequate precision to the estimate of OS rate. The precision of the estimated OS rate for a range of possible sample sizes is shown in Table 4.2.1. (Without an estimation of the proportion of censored patients, we approximated the sample size using the classical confidence interval for a proportion). Table 4.2-1: OS Rate (%) Sample Size for a Range of OS Rate with Different Precisions Precision=±4% Precision=±5% Precision=±6% 95 115 73 38 90 217 139 97 Revised Protocol No.: 01 Date: 20-Sep-2016 34 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 Table 4.2-1: OS Rate (%) CA209653 Nivolumab Sample Size for a Range of OS Rate with Different Precisions Precision=±4% Precision=±5% Precision=±6% 85 307 196 137 80 385 246 171 75 451 289 201 70 505 323 225 65 547 350 243 60 577 369 257 55 595 381 265 50 601 385 267 Abbreviation: OS=overall survival. In the CheckMate 025 trial, the 1-year overall survival rate for patients treated with nivolumab was 74.4% with a median overall survival of 25.0 months (95% CI, 21.8 to not estimable). With at least 323 patients, assuming a similar rate of 70%, the proportion of patients still alive at 1 year will be estimated with a precision of ±5.0%. This precision is considered sufficient go gain relevant conclusions. Analysis of smaller subpopulations for secondary endpoints will lead to larger confidence intervals. This study is descriptive and will explore several variables, in different subgroups, at different periods. For qualitative variables (eg, line of treatment, survival proportions, mutational status, treatment postponements, presence of AEs), the precision will depend on the number of available patients (after excluding non-exploitable patients, lost-to-follow-up patients, patients with missing data, etc) and on the size of the subgroup, as well as on the observed proportion itself. The calculated sample size of at least 323 patients has the objective of obtaining a precision of at least ±5% for the baseline (ie, at nivolumab initiation) analyses; other subgroup sizes and sample sizes during follow-up are more difficult to predict. Smallest sample sizes will lead to less precision of estimates. 4.2.1 Physician Sample Size Physicians are asked to enroll eligible patients consecutively until the maximum inclusion threshold is reached or at the end of a 2-year enrollment inclusion period (whichever occurs first). This is based on the assumption that participating physicians will be able to record an average of 6.8 eligible patients over the enrollment period of 2 years. 5 STUDY LIMITATIONS/STRENGTHS As any observational research this study is subject to a series of risks of bias. The potential major ones have been explored and taken into account as much as possible in the design and analyses. Revised Protocol No.: 01 Date: 20-Sep-2016 35 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab 5.1 Limitations 5.1.1 Threats to Representativeness The target population (the entire set of individuals to which the findings of the study are to be extrapolated) of this study is the population of patients treated by nivolumab, in the real life setting in Germany. A representative sample of the target population will be constituted using multistage sampling, in which physicians from eligible hospitals are to identify and recruit the patients. Sample representativeness may be compromised by selection biases. Site representativeness: All eligible sites, ie, hospitals and private practices, are to be considered for this study. Optimally, all sites prescribing nivolumab for RCC should be considered as eligible. No official comprehensive list of such hospitals exists in Germany. A list, therefore, will need to be established especially for the study, with a potential risk to not being fully comprehensive. Based on the sources used to establish this list, ie, input from pre-marketing clinical studies and external advisors including steering committee members, it is considered that this risk is limited. Sample of selected sites based on a global sampling method applied to the whole site sampling database might not be fully representative of German practice in terms of geographic distribution and typology of settings. Therefore, a stratified sampling approach will be used so that site selection will be balanced regarding geography and capabilities. In addition, hospitals, services and/or physicians solicited to participate might refuse. This may limit the representativeness of the study results. This will be examined by comparing active with non-participating or non-active hospitals/physicians based on sites characteristics that will be collected. Patient representativeness: Eligible patients whom physicians fail to include in the study may limit the representativeness of the study results. This will be minimized by training investigators with clear instructions and recommendations on methodological requirements regarding patient sampling. On-site or remote study initiations are planned for this study to improve the quality of training. On a related note, physicians may be inclined to include only their “best” patients in the cohort. This risk is reduced by asking the physicians to include all consecutive patients in the cohorts Patients that refuse to participate may limit the representativeness of the study results. This risk is considered to be low as patients will receive care as per label and will not have additional tests or visits to be carried out. Information bias: The conduct of the study may cause physicians to adjust their practice regarding nivolumab treatment and RCC management. As only patients initiating nivolumab are to be included in the study (to eliminate other sources of bias, such as survival bias and healthy user effects), no Revised Protocol No.: 01 Date: 20-Sep-2016 36 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab comparison can be made to “prevalent” patients (such a comparison would have been susceptible to the aforementioned biases). Attrition bias: Patients lost to follow-up are the main source of attrition bias in cohort studies. Attrition can threaten sample representativeness if patients lost to follow-up differ from the other patients, in their baseline characteristics or in their outcomes. Should the proportion of patients lost to follow-up be non-negligible, the target precision will not be reached. Moreover, the more patients lost to follow-up, the more important the threat to patient representativeness. In order to minimize the risk and potential impact, if a patient is lost to follow-up, efforts will be undertaken to collect the data from the previous visit and physicians will be encouraged to contact the patient to receive survival information. The vital status of patients lost to follow-up will be sought. Physicians will also complete a discontinuation CRF to document the reason for discontinuation from the study. Statistical analyses may address at least in part, some of the threats to patient representativeness, by reweighting the patients according to their probability of being included in the sample. 5.1.2 Other Study Limitations Missing data: missing data can bias the descriptions if data is not missing completely at random. Even in this case, missing data will have an impact on the precision of the estimates. The use of an eCRF, including online checks for missing information should reduce the risk of missing data. It will ensure that missing data will limit to non-existing information and exclude non-reported information. Sensitivity analyses will be carried out to estimate the impact of missing data on the study’s estimates. Available case analysis will be carried out in this study. Using this method, only the cases with available information (no missing data) on the variable will be described. Available case analysis has an impact on the precision of the estimates, since the number of patients used for the estimation is lower than the total number of included patients (with or without missing data). This impact, however, has been taken into account when estimating the sample size. Recall bias is an inherent limitation of questions asking about the past, especially about initial RCC diagnosis. If a recall bias is suspected, the distribution of historical variables will be described according to the time from initial diagnosis to nivolumab initiation. Partially linked to recall bias in this context, social desirability bias could be suspected for a few variables collected in the study. With regard to tobacco exposure, patients may minimize their actual tobacco consumption. With regard to health status/quality of life, patients may also minimize their actual health status severity as assessed by Quality of Life questionnaires to please their treating physician and give reassurance about the treatment’s effectiveness. However, it was considered that this behavior would be of limited impact in the specific case of the used EQ-5D questionnaires. Revised Protocol No.: 01 Date: 20-Sep-2016 37 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab Measurement error and misclassification: to limit the risk of measurement error, clear definitions of the variables measured will be provided. As this study is non-interventional and aims at describing current practice, some measurement error is to be expected as investigators are free to use the tools they prefer for patient assessment. Progression measurement will particularly be prone to measurement error as physicians are not required to employ a unique method to measure it. The frequency of radiological assessments may be heterogeneous among sites and not all physicians may use the RECIST1.1 criteria to assess progression. Risk of over-recruitment or under-recruitment: Over-recruitment would have a budget impact but would not threaten the precision of the estimates. Risk of over-recruitment is therefore not a study limitation. Under-recruitment would be a threat to the precision of the estimates and, therefore, the usefulness of the results. This risk is due to the limited information available on nivolumab prescription in real life practice, as the drug will have entered the marked for a limited amount of time when patient enrollment will start. Furthermore, other studies can compete with patient inclusions, particularly interventional trials involving nivolumab for RCC. The risk of over- or under- recruitment will be controlled for by carefully monitoring patient inclusions and modifying the enrollment period and/or maximum allowed number of inclusions per investigator if necessary. Increasing the sample size of physicians is also considered as an option, if possible. 5.1.3 Conclusion on Study Limitations Major biases or limitations have been investigated, and most of them were taken into account in the design of the study. In case some of them are not controlled during the data collection period, they will be taken into account during statistical analysis. 5.2 Strengths This is the first collection of real world data of patients with advanced RCC, who start a new systemic therapy with nivolumab for the first time within the market authorization approval in Germany. The safety data and the data regarding management and outcome of treatment-related AEs are expected to meet the high request of information of HCPs. Generalizability of study results: Patients will be enrolled and treated as per approved label for RCC. The site selection process will ensure that the sites participating are representative in regard to the German landscape of RCC treatment. The study is designed to collect data on a broad segment of patients with RCC and with minimal selection criteria for a high level of external validity. 6 STUDY CONDUCT This study will be conducted in accordance with International Society for Pharmacoepidemiology (ISPE) Guidelines for Good Pharmacoepidemiology Practices (GPP) and applicable regulatory requirements. Revised Protocol No.: 01 Date: 20-Sep-2016 38 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab Therefore, the study will adhere to the guidelines for company-sponsored post-authorization safety studies as outlined in Volume 9A of the Rules Governing Medicinal Products in the European Union: Guidelines on Pharmacovigilance for Medicinal Products for Human Use. Real-world data (RWD) is needed to generate real-world evidence (RWE) to complement those obtained from randomized clinical trials (RCTs) and to demonstrate effectiveness in both overall populations and in patient subgroups. Additionally, RWE has been used to characterize levels and patterns of use (g, dosing, regimen, indication, treatment rationales, modification in relation to management of AEs, alone, sequentially, or in combination with other drugs). Real-world data tend to be more inclusive than RCT data due to less restrictive patient inclusion criteria (eg, age, prior treatment, comorbidities, frailty) and, if follow-up is sufficient, can be a longer term approach to understanding the impact of a drug in a given target population. Therefore, data collected through prospective observational studies can be used to meet the requirements of prescribers, regulators, or payers for ongoing access to novel therapeutics. Moreover, as treatment with nivolumab is associated with the abovementioned identified risks, the assessment of safety data in the post-approval setting is of very high importance. The central aims of the study are descriptive, and are designed to capture the early post-market authorization approval period in order to describe the outcomes, patient characteristics, safety profile, and treatment patterns in adult patients with advanced RCC, who start a new systemic treatment with nivolumab for the first time, and among other subgroups of interest (age, line of therapy, Karnofsky PS, mutational status, testing flow, brain metastases, leptomeningeal carcinomatosis, history of another primary malignancy, known auto-immune disease, known hepatitis) or treatment patterns (prior palliative radiotherapy, prior nephrectomy). 6.1 Ethics Committee Review and Informed Consent 6.1.1 Ethics Committee Review The investigator must ensure that the required approvals from Ethics Committees, Independent Review Committees, Regulatory Authorities, and/or other local governance bodies are obtained before study initiation at the site. 6.1.2 Informed Consent In accordance with local regulations, subjects should provide either written or oral consent before enrollment into the study. Investigators must ensure that patients, or, in those situations where consent cannot be given by patients, their legally acceptable representatives, are clearly and fully informed about the purpose of the study, potential risks, the patient’s rights and responsibilities when participating in this study. If local regulations do not require an informed consent document to be signed by the patient, the site staff should document key elements of the informed consent process in the patient’s chart. 6.2 Responsibilities within the Study The study shall be conducted as described in this approved protocol. All revisions to the protocol must be discussed with, and be prepared by BMS. Revised Protocol No.: 01 Date: 20-Sep-2016 39 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 6.2.1 CA209653 Nivolumab Sponsor Roles and Responsibilities The study shall be conducted based on the roles and responsibilities outlined in Table 6.2.1-1. Table 6.2.1-1: Study Roles and Responsibilities Responsibilities Roles BMS Study Director/ Protocol Manager Study protocol (country specific tailoring) Overall supervision of the study Data collection in each country CRO Study dataset CRO CRO Statistical analysis: CRO Biostatistician/Global Biostatistics Lead BMS Validation of statistical plan database review and analysis data monitoring CRO Study report, results write up CRO Results CRO CRO -Participation in protocol and CRF development BMS/ CRO -Participation in publications, communication of BMS/ CRO 6.2.2 CRO Roles and Responsibilities Refer to Table 6.2.1-1. 6.2.3 External Advisory/Steering Committee An external steering committee was formed by approximately 3 to 4 external health care professionals. The steering committee is expected to provide guidance on data gaps in the treatment of RCC and to adapt this non-interventional study to the healthcare landscape in Germany. 6.3 Confidentiality of Study Data The confidentiality of records that could identify patients within the database must be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). For the purposes of protecting a patient's identity, a unique code will be assigned to each patient, such as a series of numbers and/or letters (for example, CA209653-0001-00001). The data that are recorded with the patient's assigned code are called “key-coded data”. Key-coded study data will be managed by the sponsor and/or its delegates in a study-specific electronic database (the “study database”). Only the investigator and the site staff have access to the link between patient’s assigned code and the patient’s identity. However, in case of an audit or inspection, subject to local laws and regulations, government officials, IRB/EC representatives and sponsor representatives may access this information at the study site. If the study requires on-site Revised Protocol No.: 01 Date: 20-Sep-2016 40 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab monitoring, subject to local laws and regulations, sponsor representatives will also access the primary data source at the study site (see section 6.4). Data that could directly identify the patient will not be collected in the “study database”. 6.4 Quality Control Representatives of BMS and/or its delegates must be allowed to visit all study site locations to assess the data quality and study integrity. On site, they will review study files and, if allowed by local laws and regulations, patient medical charts to compare them with source documents, discuss the conduct of the study with the investigator, and verify that the facilities remain acceptable. In addition, the study may be evaluated by BMS internal auditors and government inspectors who must be allowed access to CRFs, source documents, other study files, and study facilities. BMS audit reports will be kept confidential. The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, and promptly forward copies of inspection reports to BMS. For quality assurance, throughout the development of the study synopses and protocols, the STROBE guidelines (http://www.strobe-statement.org/) will be followed for the design and reporting of observational studies. 6.5 Database Retention and Archiving of Study Documents The investigator must retain all study records and source documents for the maximum period required by applicable regulations and guidelines, or institution procedures, or for the period specified by the sponsor, whichever is longer. The investigator must contact BMS prior to destroying any records associated with the study. Location of database and supporting documentation will be outlined in the final observational study report. 6.6 Registration of Study on Public Website This study will be registered on clinicaltrials.gov. 7 ADVERSE EVENT REPORTING 7.1 Adverse Event Definitions An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Note: Although not always adverse events by regulatory definition, the following events associated with a BMS product must be reported. Exposure (to fetus) during pregnancy, exposure (to infant) during lactation, and paternal exposure Revised Protocol No.: 01 Date: 20-Sep-2016 41 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab Overdose Lack of efficacy Abuse Misuse Off-label use Occupational exposure Medication error and potential medication error Suspected transmission of an infectious agent eg, any organism, virus or infectious particle pathogenic or non-pathogenic, via the medicinal product. The causal relationship to the BMS product under study is determined by a physician and should be used to assess all AEs. The causal relationship can be one of the following: Related: There is a reasonable causal relationship between the BMS product under study and the AE. Not related: There is not a reasonable causal relationship between the BMS product under study and the AE. The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. A non-serious adverse event is an AE not classified as serious. A serious AE (SAE) is any untoward medical occurrence that at any dose: 1. results in death 2. is life-threatening (defined as an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe) 3. requires inpatient hospitalization or causes prolongation of existing hospitalization (See Note below) 4. results in persistent or significant disability/incapacity 5. is a congenital anomaly/birth defect 6. is an important medical event (defined as a medical event(s) that may not be immediately life-threatening or result in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize the subject or may require intervention [eg, medical, surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples of such events include, but are not limited to, intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization. Suspected transmission of an infectious agent, pathogenic or nonpathogenic, via the BMS product under study is an SAE. An overdose is defined as the accidental or intentional administration of any dose of a product that is considered both excessive and medically important. Revised Protocol No.: 01 Date: 20-Sep-2016 42 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab Although pregnancy, overdose, and cancer are not always serious by regulatory definition, these events are handled as SAEs. NOTE: The following hospitalizations are not considered SAEs in BMS studies: A visit to the emergency room or other hospital department < 24 hours, that does not result in admission (unless considered an important medical or life-threatening event) Elective surgery, planned prior to signing consent Routine health assessment requiring admission for baseline/trending of health status (eg, routine colonoscopy) Medical/surgical admission other than to remedy ill health and planned prior to entry into the study Admission encountered for another life circumstance that carries no bearing on health status and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, caregiver respite, family circumstances, administrative reasons) Admission for administration of subsequent anti-cancer therapy in the absence of any other SAEs 7.2 Adverse Event Collection and Reporting Non-serious AEs and SAEs whether or not related to the BMS product under study, pregnancies, AEs associated with maternal exposure, and pregnancy outcomes ascertained in the study must be reported individually in the time frames noted below. All AEs collected will also be reported in aggregate in the final study report. All treatment-related SAEs and non-serious AEs (ie, ADRs) should be reported from signature of ICF until end of follow-up for the patient. Non-related SAE and AE should be reported until 100 days after the last administration of nivolumab. Any component of a study endpoint that is considered related to study therapy (eg, death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported as an SAE. 7.2.1 Serious Adverse Event Collection and Reporting Following the subject’s written consent to participate in the study, all SAEs, whether or not related to the BMS product under study, must be collected, including those thought to be associated with protocol-specified procedures. SAEs must be recorded on the Solicited and Noninterventional Research AE/SAE Form and reported to BMS (or designee) within 24 hours/1 business day to comply with regulatory requirements. A form should be completed for any event where doubt exists regarding its status of seriousness. Although overdose and cancer are not always serious by regulatory definition, these events should be recorded on a form and reported to BMS within 24 hours/1 business day. Revised Protocol No.: 01 Date: 20-Sep-2016 43 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab All SAEs must be reported by confirmed facsimile (fax) transmission or reported via electronic mail to: SAE Email Address: [email protected] SAE Facsimile Number: + 49 911 / 92680 8808 If only limited information is initially available, follow-up reports may be required. For studies capturing SAEs through electronic data capture (EDC), electronic submission is the required method for reporting. The paper forms should be used and submitted immediately, only in the event the electronic system is unavailable for transmission. When paper forms are used, the original paper forms are to remain on site. Related serious AEs should be reported without time limitation; non-related should be reported until 100 days after the last administration of nivolumab. If it is discovered a patient is pregnant or may have been pregnant at the time of exposure to the BMS product under study, the pregnancy, AEs associated with maternal exposure and pregnancy outcomes must be recorded on a Pregnancy Surveillance Form and reported to BMS (or designee) within 24 hours/1 business day by confirmed facsimile (fax) or reported via electronic mail to the SAE contacts provided above. If only limited information is initially available, follow-up reports may be required. The original BMS forms are to remain on site. Follow-up information should be obtained on pregnancy outcomes for 1 year following the birth of the offspring. Any pregnancy that occurs in a female partner of a male study participant should be reported to BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 7.2.2 Non-serious Adverse Event Collection and Reporting The collection of non-serious AE information should begin at initiation of the study. Non-serious AE information should also be collected from the start of the observational period intended to establish a baseline status for the subjects. Non-serious adverse events must be recorded on the Solicited and Non-interventional Research AE/SAE Form and individually reported to BMS (or designee) within 7 business days to comply with regulatory requirements. All non-serious AEs must be reported by confirmed facsimile (fax) transmission or reported via electronic mail to: Non-serious AE Email Address: [email protected] Non-serious AE Facsimile Number: + 49 911 / 92680 8808 Related non-serious AEs should be reported without time limitation; non-related should be reported until 100 days after the last administration of nivolumab. Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if they become serious. Follow-up is also required for non-serious AEs that cause interruption or Revised Protocol No.: 01 Date: 20-Sep-2016 44 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab discontinuation of the BMS product under study and for those present at the end of the study, as appropriate. Revised Protocol No.: 01 Date: 20-Sep-2016 45 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab 8 GLOSSARY OF TERMS AND LIST OF ABBREVIATIONS 8.1 Glossary of Terms Not applicable. 8.2 List of Abbreviations Term Definition AE AJCC ALT ATC codes AST BMI BMS BOR BORR CHMP CR CRC CRF CRO CT CTC CTCAE DCR DMP ECOG EDC EQ-5D EMA FKSI GFR GGT GI GPP HRQOL HRs ICD-10 Adverse event American Joint Commission on Cancer Alanine aminotransferase Anatomical Therapeutic Chemical (ATC) Classification System Aspartate aminotransferase Body mass index Bristol-Myers Squibb Company and its global affiliates Best Overall Response Best overall response rate Committee for Medicinal Products for Human Use Complete response Ethics Committee Case report form Clinical research organization Computed tomography Common Toxicity Criteria The Common Terminology Criteria for Adverse Events Disease control rate Data Management Plan Eastern Cancer Oncology Group Electronic data capture European Quality of Life-5 Dimensions European Medical Agency Functional Assessment of Cancer Therapy - Kidney Symptom Index Glomerular filtration rate Gamma-glutamyl transferase Gastrointestinal Guidelines for Good Pharmacoepidemiology Health related quality of life Hazard ratios International Statistical Classification of Diseases and Related Health Problems (version 9, 10) International Metastatic Renal Cell Carcinoma Database Consortium Institutional Review Board Immune-related response criteria IMDC IRB irRC Revised Protocol No.: 01 Date: 20-Sep-2016 46 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab Term Definition ISPE LDH M categories MCAR MedDRA MNAR MRI MSKCC N categories NCDR NCI NRAS ORR OS PD PFS PR PRO PS PT QoL RCC RCT RECIST RWD RWE SAE SAP SD T categories TNM staging TSH VAS VHL WBC WHO International Society for Pharmacoepidemiology Lactate dehydrogenase Metastasis categories Missing completely at random Medical Dictionary for Regulatory Activities Missing not at random Magnetic resonance imaging Memorial Sloan Kettering Cancer Center Lymph node categories National Cancer Data Repository National Cancer Institute NRAS is an enzyme that in humans is encoded by the NRAS gene. Overall response rate Overall survival Progressive disease Progression-free survival Partial response Patient reported outcomes Performance status Preferred term Quality of life Renal cell carcinoma Randomized controlled trial Response Evaluation Criteria in Solid Tumors Real-world data Real-world evidence Serious AE Statistical Analysis Plan Stable disease Tumor categories Tumor, node, metastasis Thyroid-stimulating hormone Visual acuity scale Von Hippel-Lindau White blood count World Health Organization Revised Protocol No.: 01 Date: 20-Sep-2016 47 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 9 CA209653 Nivolumab REFERENCES 1 EMA. CHMP Summary of opinion. http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/human/003 985/WC500202375.pdf. 2016. 2 Motzer RJ, Escudier B, McDermott DF, et al. CheckMate 025 Investigators. Nivolumab versus Everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373(19):1803-13. 3 Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized Phase II trial. J Clin Oncol 2015;33(13):1430-7. 4 Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD 1 antibody in cancer. N Engl J Med 2012;366(26):2443-54. Revised Protocol No.: 01 Date: 20-Sep-2016 48 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 APPENDIX 1 CA209653 Nivolumab HR QOL QUESTIONNAIRES FKSI-19 Utility (EQ-5D-3L) European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Revised Protocol No.: 01 Date: 20-Sep-2016 49 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab NCCN-FACT FKSI-19 (Version) Below is a list of statements that people with your illness have said are important. Please circle or mark one number per line to indicate your response as it applies to the past 7 days. not at all Revised Protocol No.: 01 Date: 20-Sep-2016 a little somebit what quite a bit very much 50 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab Utility (EQ-5D-3L) European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Revised Protocol No.: 01 Date: 20-Sep-2016 51 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 CA209653 Nivolumab Revised Protocol No.: 01 Date: 20-Sep-2016 52 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 APPENDIX 2 CA209653 Nivolumab TNM STAGING SYSTEM: TNM CLASSIFICATION FOR RCC The American Joint Committee on Cancer (AJCC) - TMN Classification for Renal Cell Carcinoma Primary tumors (T) Tx Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumor ≤ 7 cm in greatest dimension, limited to the kidney T1a Tumor ≤ 4 cm in greatest dimension, limited to the kidney T1b Tumor > 4 cm but ≤ 7 cm in greatest dimension, limited to the kidney T2 Tumor > 7 cm in greatest dimension, limited to the kidney T2a Tumor > 7 cm but ≤ 10 cm in greatest dimension, limited to the kidney T2b Tumor > 10 cm in greatest dimension, limited to the kidney T3 Tumor extends into major veins or perinephric tissue but not into the ipsilateral adrenal gland and not beyond the Gerota fascia T3a Tumor grossly extends into the renal vein or its segmental (muscle-containing) branches, or tumor invades perirenal and/or renal sinus fat but not beyond the Gerota fascia T3b Tumor grossly extends into the vena cava below the diaphragm T3c Tumor grossly extends into the vena cava above the diaphragm or invades the wall of the vena cava T4 Tumor invades beyond the Gerota fascia (including contiguous extension into the ipsilateral adrenal gland) Regional Lymph Node (N) Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in regional lymph node(s) Distant Metastasis (M) M0 No distant metastasis M1 Distant metastasis Anatomic Stage/Prognostic Groups Stage I II III IV T N M T1 T2 T1-2 T3 T4 Any T N0 N0 N1 N0-1 Any N Any N M0 M0 M0 M0 M0 M1 Source: http://www.cancer.gov/types/kidney/hp/kidney-treatment-pdq#section/_7 AJCC: Kidney. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 479-89. Revised Protocol No.: 01 Date: 20-Sep-2016 53 Approved v 2.0 930102492 2.0 Observational Study Protocol BMS-936558 APPENDIX 3 CA209653 Nivolumab CTC SEVERITY GRADING The event severity will be graded according to the NCI CTCAE Grading System, Version 4.8: Grade 1: Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate: minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental activities of daily living (ADL). Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bed ridden. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE. Not all grades are appropriate for all AEs. Therefore, some AEs are listed with fewer than 5 options for grade selection. Grade 5 (Death) is not appropriate for some AEs and therefore is not an option. Revised Protocol No.: 01 Date: 20-Sep-2016 54 Approved v 2.0 930102492 2.0
