邢唷��>�  f����]^_`abcdep�k�������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������欹�U ��诿bjbj雗雗 F��閍�閍��������ff�#�#�#�#�#�����#�#�#8.$�*&��#Q���+2.p�.�.�.�1�V5L�6�|�~�~�~�~�~�~�$1��缙`⒗i�#婨n1@�1婨婨⒗�#�#�.�.� �荓荓荓婨r�#�.�#�.|�荓婨|�荓荓��j��.����@�摃�����鼺�Ph�!�0Q�J� G�鱃nG��j�j�VG��#啦� J7��;8荓?�楢�J7J7J7⒗⒗eJbJ7J7J7Q�婨婨婨婨��������������������������������������������������������������������G�J7J7J7J7J7J7J7J7J7fB �": TREATMENT-RADIOTHERAPY TEMPLATE INSTRUCTIONS v. 11/26/2018 The protocol template is a tool to facilitate rapid protocol development. It is not intended to supersede the role of the Principal Investigator in the authoring and scientific development of the protocol. It contains the 揵oilerplate� language commonly required. Content may be modified as necessary to meet the scientific aims of the study and development of the protocol. For further details and examples, please refer to the reference document located:  HYPERLINK "/cancer/research/clinical-research-office/protocol-templates" /cancer/research/clinical-research-office/protocol-templates The BLUE text is meant to provide instructions and examples, please delete the BLUE instructions and examples and replace them with protocol specific designs. Please refer to CCCC PRMC website for comprehensive list of definitions and examples for each protocol section.   STUDY NUMBER: CASE XXXX Number will be assigned by Cancer Center at time of PRMC Submission ClinicalTrials.gov NCT #: TBD Protocol Date: STUDY TITLE: Full study title here (600 characters maximum) PRINCIPAL INVESTIGATOR: A study can only have one Principal Investigator. Trials that are being conducted at both University Hospitals and Cleveland Clinic will list the Principal Investigator at the Lead Institution as the overall Principal Investigator for the study. The Co-PI(s) refer to the physician(s) who will lead the study at non-lead institution(s). Example: Joint Protocol with UH Lead PRINCIPAL INVESTIGATOR: Name of Physician, MD Case Comprehensive Cancer Center University Hospitals Cleveland Medical Center Seidman Cancer Center 11100 Euclid Avenue Cleveland, OH 44106 Telephone including area code Email address CO-PI: Name of Physician, MD Case Comprehensive Cancer Center Cleveland Clinic Taussig Cancer Center 9500 Euclid Avenue Cleveland, OH 44195 Telephone including area code Email address CO- INVESTIGATOR: List co-investigators alphabetically by site in the following order: Case Comprehensive Cancer Center, Lead Institution, Main Site Case Comprehensive Cancer Center, Lead Institution, Regional Sites Case Comprehensive Cancer Center, Non-Lead Institution, Main Site Case Comprehensive Cancer Center, Non-Lead Institution, Regional Sites *If this is a multi-institutional study, the protocol title page should include the name of each participating institution, the investigator responsible for the study at that institution, and his/her telephone # and e-mail address. STATISTICIAN: Name of Statistician, degree Case Comprehensive Cancer Center Name of Institution Street Address City, State, Zip code Telephone including area code Email address STUDY COORDINATOR: Name of Lead Study Coordinator Case Comprehensive Cancer Center Name of Institution Street Address City, State, Zip code Telephone including area code Email address SPONSOR: Case Comprehensive Cancer Center SUPPORT/FUNDING: List any support/grants or any funding source (partial or full) here SUPPLIED AGENT(S): Name of supplied agents and supplier, if applicable IND #: If applicable OTHER AGENT(S): Name of other agents Title: Principal Investigator: PRINCIPAL INVESTIGATOR SIGNATURE: ___________________________________ Date: ___________________ SUMMARY OF CHANGES Please provide a list of changes from the previous approved version of the protocol starting at IRB approval. This table will remain blank until initial IRB approval. The list shall be a brief overview. When appropriate, a brief justification for the change should be included. This is a running list for the life of the study. Protocol DateSectionChangeInitial IRB approvalSummarize changes to first protocol amendment STUDY SCHEMA Please provide a visual schema for the study. If preferred, a summary or synopsis may be provided. HYPERLINK "../../nkovach2/AppData/Local/Microsoft/Users/ecollin0/AppData/Local/Microsoft/Windows/Temporary Internet Files/OLK188A/EXAMPLE TREATMENT SCHEMAS.doc"EXAMPLE STUDY SCHEMA - hyperlink to separate document Protocol Synopsis: Please refer to  HYPERLINK "http://cancer.case.edu/cancer/media/caseedu/cancer-center/docs/clinical-res-office/protocol-templates/Protocol%20Summary.pdf" PROTOCOL SUMMARY guidance document for examples PROTOCOL SUMMARY Protocol Number/TitleCase CCC assigned number/TitleStudy PhaseStudy phase as defined by clinicaltrials.govBrief Background/Rationale Include: Why doing this study on this population with this drug. Incidence/burdenPrimary Objective Primary Endpoint(s) Endpoints: how it will be measured and at what time point. Do not use 揺nd of study� or 揳t progression�.Secondary Objective(s)Secondary Endpoint(s)Exploratory Objective(s)Exploratory Endpoints (s) This is where exploratory research endpoints will go. For example, gathering preliminary dataCorrelative Objective(s) Correlative Endpoint(s) This is where correlative study objectives will go. Pharmacokinetics, Pharmacodynamics, and biomarkers, etc.Sample SizeNumber expected to accrue Age, genderDisease sites/ConditionsICD terminologyInterventionsAgent X, route, dose, cycle length, number of cyclesAgent Y, route, dose, cycle length, number of cycles ABBREVIATIONS Please update table with relevant abbreviations used in the protocol CCCCCase Comprehensive Cancer CenterCRFCase Report FormDCRUDahm抯 Clinical Research UnitDSTCData Safety and Toxicity CommitteeFDAFood and Drug AdministrationICFInformed Consent FormIRBInstitutional Review BoardPRMCProtocol Review and Monitoring CommitteeSOCStandard of CareCCFCleveland Clinic FoundationUHUniversity Hospitals TABLE OF CONTENTS 1.0 INTRODUCTION 1.1 Background of Study Disease 1.2 Preclinical Data 1.3 Clinical Data to date 1.4 Rationale 1.5 Background and rationale of correlative studies 2.0 OBJECTIVES 2.1 Primary Objective 2.2 Secondary Objective(s) 2.3 Exploratory Objective(s) 3.0 STUDY DESIGN 3.1 Study design, dose escalation, and cohorts 3.2 Number of Subjects 3.3 Replacement of Subjects 3.4 Expected Duration of Treatment and Subject Participation 4.0 SUBJECT SELECTION 4.1 Inclusion Criteria 4.2 Exclusion Criteria 4.3 Inclusion of Women and Minorities 5.0 REGISTRATION 6.0 TREATMENT PLAN 6.1 Radiation Therapy 6.1.1 General Guidelines and Timing 6.1.2 Equipment and Techniques to be Used 6.1.3 Target Volumes 6.1.4 Dose Target and Organs at Risk Constraints 6.2 Name of Investigational Agent X Administration 6.3 Name of Standard of Care Agent(s) Administration 6.4 Phase I Dose Escalation 6.5 Definition of Dose Limiting Toxicity 6.6 General Concomitant Medications and Supportive Care Guidelines 6.7 Criteria for Removal from Study 6.8 Duration of Follow-Up 7.0 DOSE DELAYS / DOSE MODIFICATIONS 8.0 ADVERSE EVENTS AND POTENTIAL RISKS 8.1 Radiation Therapy Adverse Events 8.2 Agent X/Y Adverse events 8.3 Definitions 8.4 Serious Adverse Event Report Form 8.5 Reporting Procedures for Serious Adverse Event 8.6 Serious Adverse Events and OnCore� 8.7 Data Safety Toxicity Committee 8.8 Data and Safety Monitoring Plan 9.0 PHARMACEUTICAL INFORMATION 9.1 Investigational Agent(s) 9.2 Commercial Agent(s) 10.0 CORRELATIVE/EXPLORATORY 10.1 Name of Correlative/Exploratory Study #1 10.2 Name of Correlative/Exploratory Study #2 10.3 Name of Correlative/Exploratory Study #3 11.0 STUDY PARAMETERS AND CALENDAR 11.1 Study Parameters 11.2 Calendar 12.0 MEASUREMENT OF EFFECT choose appropriate measurement of effect; ie. RECIST (solid tumors) / hematologic diseases / other response measurement 13.0 RECORDS TO BE KEPT/REGULATORY CONSIDERATIONS 13.1 Data Reporting 13.2 Regulatory Considerations 14.0 STATISTICAL CONSIDERATIONS REFERENCES APPENDICES The investigator may choose from the following commonly used appendices and modify per protocol specifications. The investigator must supply additional appendices as needed including questionnaires and surveys. For further resources, please see reference document ____) APPENDIX __ ECOG / Karnofsky Performance Status Criteria APPENDIX __ Subject Diary (pill, injectable, etc) 1.0 Introduction 1.1 Background Please provide background, incidence, and treatment information on the study disease. Please be specific in the title for disease specific studies. Example: 揂dvanced Biliary Cancers� versus 揂dvanced Cancers� 1.2 Preclinical Data Provide background and brief information for agent X. Include any animal studies, the explanation of the mechanism of action, and any preclinical data about the agent or treatment. 1.3 Clinical Data to Date Summarize the available clinical study data with relevance to the protocol under development. If none is available, include a statement that there is no available clinical research data to date on the investigational product. 1.4 Rationale Please provide the background and rationale for evaluating this (combination) therapy in this disease. Include the rationale for the proposed starting doses and dose escalation scheme as well as route of administration and dosage period. 1.5 Background and rationale of correlative studies Please provide the background and rationale for correlative studies and exploratory endpoints. 2.0 Objectives Describe the overall objectives and purpose of the study, keeping in mind that objectives must be measurable. Records to be kept should capture the measurement. Study parameters (calendar) should indicate when captured. 2.1 Primary Objective It is preferable to have only one primary objective and primary endpoint. What scientific question are you trying to answer? HYPERLINK "../../nkovach2/AppData/Local/Microsoft/Users/ecollin0/AppData/Local/Microsoft/Windows/Temporary Internet Files/OLK188A/EXAMPLE OBJECTIVES.doc"Example: Hyperlink to examples 2.2 Secondary Objective(s) HYPERLINK "../../nkovach2/AppData/Local/Microsoft/Users/ecollin0/AppData/Local/Microsoft/Windows/Temporary Internet Files/OLK188A/EXAMPLE OBJECTIVES.doc"Example: Hyperlink to examples 2.3 Exploratory Objectives (s) HYPERLINK "../../nkovach2/AppData/Local/Microsoft/Users/ecollin0/AppData/Local/Microsoft/Windows/Temporary Internet Files/OLK188A/EXAMPLE OBJECTIVES.doc"Example: Hyperlink to examples 3.0 Study Design Please provide an overview of the study design and the rationale for this type of design. 3.1 Study design including dose escalation / cohorts This section should include: the type of trial design of the study, stages, cohort information, how subjects will be randomized and if there are plans to use a placebo. Please see guidance document for examples of blinding/unblinding procedures. 3.2 Number of Subjects Provide the number of subjects that will be included in the study using a sentence format. Example: Approximately 50 subjects will be enrolled in this trial. Example if more than one phase: Approximately 50 subjects will be enrolled in this trial. Approximately 15 will be enrolled in the phase I part and 35 in the phase II part. 3.3 Replacement of Subjects The replacement of subjects is protocol specific and needs to be tailored to the trial. Example: If Oral Drug is to be taken 21 out of 21 days and this is not met: Example: If a subject does not take at least 17 doses in the first cycle, the subject will be replaced because he/she has not taken enough drug to confirm safety at that dose level. HYPERLINK "../../nkovach2/AppData/Local/Microsoft/Users/ecollin0/AppData/Local/Microsoft/Windows/Temporary Internet Files/OLK188A/EXAMPLE OF REPLACEMENT OF SUBJECTS.doc"Example: Hyperlink to further examples 3.4 Expected Duration of Treatment and Subject Participation Please provide a brief summary of the length of treatment period, plus the length of follow up period and any study windows that are applicable. Please provide length of each cycle, minimum and maximum number of cycles. If treatment can continue until disease progression (i.e. no maximum number of cycles), please indicate here. If clinical benefit is not likely until after a certain number of cycles, specify that here. Treatment duration may be modified per section ___. 4.0 Subject Selection Each of the criteria in the sections that follow must be met in order for a subject to be considered eligible for this study. Use the eligibility criteria to confirm a subject抯 eligibility. For UH lead CASE Studies, please use signature lines below. For CCF lead CASE studies, please remove. Subject抯 Name _____________________________________________________________ Medical Record # ___________________________________________________________ Research Nurse / Study Coordinator Signature: _________________________________________________ Date __________ Treating Physician [Print] ____________________________________________________ Treating Physician Signature: _________________________________________________ Date __________ Hyperlink to Inclusion/Exclusion tips and examples 4.1 Inclusion Criteria Inclusion Criteria must describe the subject population that you want to include in the study. Each statement must be able to be placed into the form of a question with a 損ositive� response received. Create a numbered list of criteria applicable to the protocol that subjects must meet to be eligible for study enrollment. Subjects must meet all of the following inclusion criteria to be eligible for enrollment: Below are common examples: Edit per protocol or see further examples hyperlinked above. 4.1.1 Subjects must have histologically or cytologically confirmed Name of Disease. Please specify eligible disease(s)/stage(s)/prognostic score(s) as well as if staging is pathological or clinical. 4.1.2 Subjects must have received (no, no more than X) prior therapies for this disease. **If applicable, provide guidance on what constitutes a prior line of therapy, how to count prior lines of therapy and breaks in therapy. 4.1.3 Age >18 years. Please state reason for age restriction. If applicable, the following text can be used;  Because no dosing or adverse event data are currently available on the use of ______ in combination with _______ in subjects d"18 years of age, children are excluded from this study. 4.1.4 Performance status _____ [See Appendix __]. Choose one method (not both): Example: ECOG Performance status d" 2 Example: Karnofsky Performance status e" 60% 4.1.5 Life expectancy of e" # weeks/months, in the opinion of and as documented by the investigator. 4.1.6 Subjects must have normal organ and marrow function as defined below: Add time frame if applicable. Please review for relevance to the specific study and modify. 4.1.6.1 Hemoglobin e" 10.0 g/dl 4.1.6.2 Leukocytes e" 3,000/mcL 4.1.6.3 Absolute neutrophil count e" 1,500/mcL 4.1.6.4 Platelet count e" 100,000/mcL 4.1.6.5 Total bilirubin within normal institutional limits 4.1.6.6 AST (SGOT) d" 2.5 X institutional upper limit of normal 4.1.6.7 ALT (SGPT) d" 2.5 X institutional upper limit of normal 4.1.6.8 Serum creatinine within normal institutional limits 4.1.7 Please insert other appropriate eligibility criteria. 4.1.8 Sex (defined as a person抯 classification as male or female based on biological distinctions) 4.1.9 Gender based (defined as self-representation of gender identity). If eligibility is based on gender, describe gender criteria. 4.1.10 Subjects must have the ability to understand and the willingness to sign a written informed consent document. 4.2 Exclusion Criteria Exclusion Criteria must describe the subject population that you do NOT want to include in the study. Each statement must be able to be placed into the form of a question with a 搉egative� response received. Create a numbered list of criteria applicable to the protocol that would exclude a subject from study enrollment. The presence of any of the following will exclude a subject from study enrollment. Below are common examples: Edit per protocol or see further examples hyperlinked above. 4.2.1 Prior treatment toxicities resolved to d" Grade X according to NCI CTCAE Version 4.0 (list exceptions, e.g. alopecia, neuropathy, etc). 4.2.2 Subjects receiving any other investigational agents. 4.2.3 To be included if applicable to protocol. Suggested text is provided below: Subjects with untreated brain metastases/CNS disease will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. 4.2.4 History of allergic reactions attributed to compounds of similar chemical or biologic composition to Agent X or other agents used in this study. 4.2.5 Please state appropriate exclusion criteria relating to concomitant medications or substances that have the potential to affect the activity or pharmacokinetics of the study agent(s). 4.2.6 Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. 4.2.7 The investigator must state a medical or scientific reason if pregnant or nursing subjects will be excluded from the study. Suggested text is provided below: Pregnant or breastfeeding women are excluded from this study because Agent X is Name of Agent Class agent with the potential for teratogenic or abortifacient effects. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with Agent X, breastfeeding should be discontinued if the mother is treated with Agent X. These potential risks may also apply to other agents used in this study. 4.2.8 The investigator must state a medical or scientific reason if subjects who are HIV-positive will be excluded from the study. Suggested text is provided below: HIV-positive subjects on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with Agent X. In addition, these subjects are at increased risk of lethal infections when treated with marrow suppressive therapy. Appropriate studies will be undertaken in subjects receiving combination antiretroviral therapy when indicated. Also include whether HIV testing is required for this study, or only if a known diagnosis will be excluded. 4.2.9 Insert other appropriate agent-specific exclusion criteria. 4.3 Inclusion of Women and Minorities Make sure you include the appropriate verbiage for the subject population. Suggested text is provided below: Men, women and members of all races and ethnic groups are eligible for this trial. 5.0 Registration All subjects who have been consented are to be registered in the OnCore� Database. For those subjects who are consented, but not enrolled, the reason for exclusion must be recorded. All subjects will be registered through [Name of Lead Site] and will be provided a study number by contacting the study coordinator listed on the cover page. Include if a registration form will be required. If the trial is randomized the method of randomization should be stated as well as the proportion of subjects that will be accrued to each dose level. Example: Subjects will be randomized equally to the four dose levels being studied using permuted blocks. 6.0 Treatment Plan Briefly describe the treatment regimen planned. If there are different cohorts, label each cohort and appropriate treatment schedule: Pre-medications allowed/required/suggested (if applicable) Agent(s) (if applicable) Dose(s) (of agents and RT) Route of administration Treatment schedule (including pre-treatment prep) Treatment duration Please provide separate regimen descriptions for different treatment groups of subjects as necessary. The investigator must include the following statement if treatment is required to be administered only on an inpatient basis: Treatment must be administered only on an inpatient basis. Radiation Therapy 6.1.1 General Guidelines and Timing Describe the general rationale for radiation therapy and indications. Describe how radiation will be scheduled relative to chemotherapy administration if applicable. 6.1.2 Equipment and Techniques to be used Provide details of treatment machine(s) (linear accelerator, proton beam, cyberknife, gamma knife) and techniques to be utilized (IMRT, TBI, SBRT, 3D CRT, etc). Describe immobilization, simulation, motion management approach, image fusion, and other techniques. 6.1.3 Target Volumes Provide details on GTV, CTV and PTV and/or other target description as applicable. 6.1.4 Dose to Target and Organs at Risk Constraints Provide details on prescribed dose and fractionation. Include prescription points, coverage goals and dose limits on OARs. 6.2 Name of Investigational Agent X Administration (If applicable, for studies using investigational chemotherapy agents or investigational agent combinations) In addition to a dosing schema, please add a narrative description of the investigational agent administration. Investigational Agent Administration Example: Subjects will receive Agent X ___ mg/m2 on Days 1-3 of each (28 day) cycle. Name of Agent will be administered IV over 2 hours. Example: Subjects will receive Agent Y ___ mg/m2 by IV on Day 1 of each 21-day cycle. Prior to each Name of Agent treatment, pre-hydrate with at least 1000 ml normal saline and use diuretics per institutional guidelines. Example: Subjects will receive Agent Z ____mg/m2 by IV on days 1, 2, and 3 of each 21-day cycle. Please add subsequent sections for additional investigational agents or agent combinations. 6.3 Name of Standard of Care Agent(s) Administration (If applicable, for studies using Standard of Care chemotherapy agents or standard of care agent combinations) In addition to a dosing schema, please add a narrative description of the non-investigational agent administration in the same format as above. SOC Example: Subjects will receive Agent X ___ mg/m2 on Days 1-3 of each (28 day) cycle. Agent X will be administered IV over 2 hours. Example: Subjects will receive Agent Y ___ mg/m2 by IV on Day 1 of each 21-day cycle. Prior to each Agent Y treatment, pre-hydrate with at least 1000 ml normal saline and use diuretics per institutional guidelines. Example: Subjects will receive Agent Z ___ mg/m2 by IV on days 1, 2, and 3 of each 21-day cycle. 6.4 Phase I Dose Escalation (if applicable) Dose escalation will proceed within each cohort according to the following scheme. Dose-limiting toxicity (DLT) is defined in section 6.5. Number of Subjects with DLT at a Given Dose LevelEscalation Decision Rule0 out of 3Enter 3 subjects at the next dose level.1 out of 3Enter at least 3 more subjects at this dose level. If 0 of these 3 subjects experience DLT, proceed to the next dose level. If 1 or more of this group suffer DLT, then dose escalation is stopped, and this dose is declared the maximally administered dose. Three (3) additional subjects will be entered at the next lowest dose level if only 3 subjects were treated previously at that dose.>2Dose escalation will be stopped. This dose level will be declared the maximally administered dose (highest dose administered). Three (3) additional subjects will be entered at the next lowest dose level if only 3 subjects were treated previously at that dose.<1 out of 6 at highest dose level below the maximally administered doseThis is generally the recommended phase 2 dose. 365bet体育在线世界杯 least 6 subjects must be entered at the recommended phase 2 dose. 6.5 Definition of Dose-Limiting Toxicity (Applicable for dose escalation studies only) Dose limiting toxicities must be suspected to be related to the investigational product (please refer to section __ for all other dose modifications). For dose escalation studies, please provide explicit definitions of the type(s), grade(s), and duration(s) of adverse events that will be considered dose-limiting toxicity(s), or provide definitions of other endpoints that will be used to determine dose escalations. Management and dose modifications are outlined in Section 7. 6.6 General Concomitant Medications and Supportive Care Guidelines State guidelines for use of which concomitant medicines/therapies are permitted during the study, and which concomitant medicines/therapies are not permitted during the study (if applicable). Include any additional rescue therapies or supportive care medications or treatments required for administration of each agent in the treatment. Suggestive text, as applicable for supportive care: Subjects should receive full supportive care, including transfusions of blood and blood products, cytokines, antibiotics, antiemetics, etc when appropriate. Example: Because there is a potential for interaction of Name of Agent(s) with other concomitantly administered drugs through the cytochrome P450 system, the case report form must capture the concurrent use of all other drugs, over-the-counter medications, or alternative therapies. The Principal Investigator should be alerted if the subject is taking any agent known to affect or with the potential to affect selected CYP450 isoenzymes. Please refer to Appendix _____ for a complete list. 6.7 Criteria for Removal from Study In the absence of treatment delays due to adverse events, treatment may continue for # cycles or until one of the following criteria applies: � Disease progression, � Intercurrent illness that prevents further administration of treatment, � The investigator considers it, for safety reasons, to be in the best interest of the subject. � Unacceptable adverse event(s) [be specific] Example: Unacceptable treatment related toxicity, NCI CTC AE version 4.0 Grade 3 or 4 that fails to recover to baseline or < Grade 3 in the absence of treatment within 4 weeks Example: Any toxicity or other issue that causes a delay of study drug administration by more than 4 weeks � General or specific changes in the subject抯 condition render the subject unacceptable for further treatment in the judgment of the investigator, � Subject decision to withdraw from treatment (partial consent) or from the study (full consent), � Pregnancy during the course of the study for a child-bearing participant � Death, or � Sponsor reserves the right to temporarily suspend or prematurely discontinue this study. The date and reason for discontinuation must be documented. Every effort should be made to complete the appropriate assessments. 6.8 Duration of Follow Up Investigators must be sure to match the duration of follow-up with the calendar regardless if survival is the endpoint of a study. Please indicate here if the sponsor-investigator intents to capture information after a patient withdraws from study (per patient agreement). Subjects will be followed for toxicity for 30 days (minimum suggested time frame, follow up time frame should be appropriate to the metabolism of the product) after treatment has been discontinued or until death, whichever occurs first. The clinical course of each event will be followed until resolution, stabilization, or until it has been determined that the study treatment or participation is not the cause. [The investigator may want to consider a cut off of 6 months.] Serious adverse events that are still ongoing at the end of the study period will necessitate follow-up to determine the final outcome. Any serious adverse event that occurs after the study period and is considered to be possibly related to the study treatment or study participation will be recorded and reported immediately. 7.0 Dosing Delays/Dose Modifications Treatment modifications/dosing delays and the factors predicating treatment modification should be explicit and clear. If dose modifications or radiation treatment delays are anticipated, please provide a dose de-escalation schema. If you plan to allow dose re-escalation for 1 or more agents, please specify dose re-escalation process in this section. All treatment modifications must be expressed as a specific dose or amount rather than as a percentage of the starting or previous dose. Please consider dosing formulation when calculating dose modifications for ORAL agents. Dose modifications/treatment delays may be presented separately or together as appropriate. Please see examples of dosing delays and modifications in the guidance document. 8.0 Adverse Events and Potential Risks 8.1 Radiation Therapy For RT, please include a comprehensive list of all reported adverse events and any potential risks. 8.2 Agent X/Y For treatment agents, please include a comprehensive list of all reported adverse events and any potential risks for each agent (such as the toxicities seen with another agent of the same class or risks seen in animals administered this agent) as provided by the manufacturer/CAEPR. Please also include the recommended treatment for the commonly occurring events. This information may be provided in tabular format. For a commercial agent, please provide a list of those adverse events most likely to occur on this study, and refer the reader to the package insert(s) for the comprehensive list of adverse events. Please also include the recommended clinical management for the commonly occurring events. This information may be provided in tabular format. 8.3 Definitions 8.3.1 Adverse Event An adverse event (AE) is any unfavorable or unintended event, physical or psychological, associated with a research study, which causes harm or injury to a research participant as a result of the participant抯 involvement in a research study. The event can include abnormal laboratory findings, symptoms, or disease associated with the research study. The event does not necessarily have to have a causal relationship with the research, any risk associated with the research, the research intervention, or the research assessments. Adverse events may be the result of the interventions and interactions used in the research; the collection of identifiable private information in the research; an underlying disease, disorder, or condition of the subject; and/or other circumstances unrelated to the research or any underlying disease, disorder, or condition of the subject. 8.3.2 Serious Adverse Events A serious adverse event (SAE) is any adverse experience occurring at any dose that results in any of the following outcomes: Results in death. Is a life-threatening adverse experience. The term life-threatening in the definition of serious refers to an adverse event in which the subject was at risk of death at the time of the event. It does not refer to an adverse event which hypothetically might have caused death if it were more severe. Requires inpatient hospitalization or prolongation of existing hospitalization. Any adverse event leading to hospitalization or prolongation of hospitalization will be considered as Serious, UNLESS at least one of the following expectations is met: The admission results in a hospital stay of less than 24 hours OR The admission is pre-planned (e.g., elective or scheduled surgery arranged prior to the start of the study) OR The admission is not associated with an adverse event (e.g., social hospitalization for purposes of respite care. However it should be noted that invasive treatment during any hospitalization may fulfill the criteria of 搈edically important� and as such may be reportable as a serious adverse event dependant on clinical judgment. In addition where local regulatory authorities specifically require a more stringent definition, the local regulation takes precedent. Results in persistent or significant disability/incapacity. The definition of disability is a substantial disruption of a person抯 ability to conduct normal life抯 functions. Is a congenital anomaly/birth defect. Is an important medical event. Important medical events that may not result death, be life-threatening, or require hospitalization may be considered a serious adverse experience when, based upon appropriate medical judgment, they may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood disease or disorders, or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. The development of a new cancer is always considered an important medical event. Investigators may choose to include exclusions to Serious Adverse Events being reported. Example: For the purpose of this study the following events would not be considered adverse events and would not be recorded in the database: Abnormal laboratory findings considered associated to the original disease 8.3.3 Adverse Event Evaluation The investigator or designee is responsible for ensuring that all adverse events (both serious and non-serious) observed by the clinical team or reported by the subject which occur after the subject has signed the informed consent are fully recorded in the subject抯 medical records. Source documentation must be available to support all adverse events. A laboratory test abnormality considered clinically relevant (e.g., causing the subject to withdraw from the study, requiring treatment or causing apparent clinical manifestations, result in a delay or dose modification of study treatment, or judged relevant by the investigator), should be reported as an adverse event. The investigator or sub-investigator (treating physician if applicable) will provide the following for all adverse events (both serious and non-serious): Event term (as per CTCAE) Description of the event Date of onset and resolution Expectedness of the toxicity Grade of toxicity 365bet体育在线世界杯tribution of relatedness to the investigational therapy/agent- (this must be assigned by an investigator, sub-investigator, or treating physician) Action taken as a result of the event, including but not limited to; no changes, dose interrupted, reduced, discontinued, etc. or action taken with regard to the event, i.e. no action, received conmed or other intervention, etc. Outcome of event Descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version X will be utilized for agent AE reporting. An expected adverse event is an event previously known or anticipated to result from participation in the research study or any underlying disease, disorder, or condition of the subject. The event is usually listed in the Investigator Brochure, consent form or research protocol. An unexpected adverse event is an adverse event not previously known or anticipated to result from the research study or any underlying disease, disorder, or condition of the subject. 365bet体育在线世界杯tribution is the relationship between an adverse event or serious adverse event and the study drug. 365bet体育在线世界杯tribution will be assigned as follows: Definite � The AE is clearly related to the study drug. Probable � The AE is likely related to the study drug. Possible � The AE may be related to the study drug. Unlikely � The AE is doubtfully related to the study drug. Unrelated � The AE is clearly NOT related to the study drug. Protocol must specify if attribution is required for individual components of the treatment regimen or the treatment regimen as a whole. 8.4 SAE Report Form SAE抯 related to radiation therapy only will be recorded into OnCore and reported to IRB according to local IRB policies and procedures. SAEs related to agent therapy will be recorded on the FDA Form 3500A (MedWatch) but should only be reported as instructed below. The electronic FDA SAE reporting forms should not be used. 8.5 Reporting Procedures for Serious Adverse Events For the purposes of safety reporting, all adverse events will be reported that occur [Please insert appropriate time frame, e.g. on or following first day of RT, on day of registration, etc.] through 30 days after the final dose of study radiation therapy/drug. Adverse events, both serious and non-serious, and deaths that occur during this period will be recorded in the source documents. All SAEs should be monitored until they are resolved or are clearly determined to be due to a subject抯 stable or chronic condition or intercurrent illness(es). Related AEs will be followed until resolution to baseline or grade 1 or stabilization. 8.5.1 SAE Reporting Requirements Participating investigators (all sites) must report all serious adverse events to the Lead Site Principal Investigator (e.g. Sponsor-Investigator) within 24 hours of discovery or notification of the event. The participating investigator must also provide follow-up information on the SAE until final resolution.� Insert Lead Site PI抯 email/fax number (as applicable). Protocol coordinator can be contacted if applicable. The Lead Site Principal Investigator will review the SAE and report the event to the FDA, external collaborator(s), and IRB as applicable. It is the Sponsor-Investigator抯 responsibility (e.g. lead site PI) to ensure that ALL serious adverse events that occur on the study (e.g. ALL SAEs that occur at each enrolling institution) are reported to all participating sites. Drug Supplier / Manufacturer / Financial Supporter Reporting Requirements: Insert the external entity抯 reporting Requirements. Please include language that specifies the Sponsor-Investigator (e.g. lead site PI) will be responsible for reporting all SAEs to the external entity. Institutional Review Board Reporting Requirements: Investigative sites will report adverse events to their respective IRB according to the local IRB抯 policies and procedures in reporting adverse events. 8.6 SAEs and OnCore All SAEs will be entered into OnCore. A copy of the SAE form(s) submitted to the sponsor-investigator is also uploaded into Oncore. 8.7 Data Safety and Toxicity Committee It is the responsibility of each site PI to ensure that ALL SAEs occurring on this trial (internal or external) are reported to the Case Comprehensive Cancer Center抯 Data and Safety Toxicity Committee. This submission is simultaneous with their submission to the sponsor and/or other regulatory bodies The sponsor-investigator is responsible for submitting an annual report to the DSTC as per CCCC Data and Safety Monitoring Plan. � 8.8 Data and Safety Monitoring Plan This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and Safety Monitoring Plan in accordance with NCI guidelines. 9.0 PHARMACEUTICAL INFORMATION A list of the adverse events and potential risks associated with the investigational or commercial agents administered in this study can be found in Section #. If applicable. Pharmaceutical information must be tailored to the specific protocol. Repeat this section for all pharmaceutical agents being given. If protocol does not include any investigational agents and is RT only, add RT risks in section 9.1. The pharmaceutical section must contain at least the following information, available from the appropriate Investigator抯 Brochure or package insert: 9.1 Investigational Agents 9.1.1 Name of Agent ___________________________ Other Names: ___________________________ Product description: (e.g. doses, tablets, vials, powder, etc�- if capsules of varying doses are supplied these should be described) Packaging: (e.g. hard gelatin capsules in bottles, capsule s in blister packs, vials, etc�) Solution preparation: (how the agent is to be prepared): Describe in detail all the steps necessary to properly prepare agent. Include reconstitution directions and directions for further dilution, if appropriate. Storage requirements: Include the requirements for the original agent form, reconstituted solution, and final diluted product, as applicable. Stability: Include the stability of the original agent form, reconstituted solution, and final diluted product, as applicable. Route of administration: Include a description of the method to be used and the rate of administration, if applicable. Example: continuous intravenous infusion over 24 hours, short intravenous infusion over 30-60 minutes, intravenous bolus, etc. Describe any precautions required for safe administration. Drug Procurement: Investigational drug may or may not be supplied for a study. Please be sure to make this clear by inserting one of the statements below as applicable: Manufacturer (must specify if the Sponsor-Investigator developed the agent) When drug is not supplied: Agent X must be obtained from commercial sources. Example: Agent X must be obtained from commercial sources and is available in 500 mg/10 ampules and vials, and 1 gm/20 ml, 2.5 gm/50 ml, and 5 gm/100 ml vials. Consider including the following statement while reviewing the template: The cost of this agent will be the subject抯 responsibility. When drug is supplied: Study Agent X will be supplied for this study by Sponsor/company name. Packaging and labeling: Must specify the contents of the label if the Sponsor-Investigator developed the agent: name of drug, quantity of drug, date of packaging, recommended storage temp, lot number) Drug Accountability: To be included when drug is supplied The investigator or designated study personnel are responsible for maintaining accurate dispensing records of the study drug. All study drugs must be accounted for, including study drug accidentally or deliberately destroyed. Under no circumstances will the investigator allow the investigational drug to be used other than as directed by the protocol. If appropriate, drug storage, drug dispensing, and drug accountability may be delegated to the pharmacy section of the investigative site. Drug Destruction: To be included when drug is supplied This section should note the procedures for final reconciliation of the site抯 drug or device supply at the end of the study, and whether study drug or device is to be shipped back to a source or destroyed on site. If drug or device is to be shipped back to a source, note the address and contact information here. Suggested language: �365bet体育在线世界杯 the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and drug remaining. This reconciliation will be logged on the drug reconciliation form, signed and dated. Any discrepancies noted will be investigated, resolved, and documented prior to return or destruction of unused study drug. Drug destroyed on site will be documented in the study files.� Other Information: Include any other information, e.g., any special handling, any nursing implications, and any subject care implications. Note: if the protocol involves a placebo the sections listed above apply to all components of the protocol抯 treatment regimen (including placebo � if applicable) 9.2 Commercial Agent 9.2.1 Name of Agent ___________________________ Other Names: ___________________________ Product description: (e.g. doses, tablets, vials, powder, etc�- if capsules of varying doses are supplied these should be described) Solution preparation: (how the agent is to be prepared): Describe in detail all the steps necessary to properly prepare agent. Include reconstitution directions and directions for further dilution, if appropriate. Storage requirements: Include the requirements for the original agent form, reconstituted solution, and final diluted product, as applicable. Stability: Include the stability of the original agent form, reconstituted solution, and final diluted product, as applicable. Route of administration: Include a description of the method to be used and the rate of administration, if applicable. Example: continuous intravenous infusion over 24 hours, short intravenous infusion over 30-60 minutes, intravenous bolus, etc. Describe any precautions required for safe administration. Drug Procurement: Investigational drug may or may not be supplied for a study. Please be sure to make this clear by inserting one of the statements below as applicable: Manufacture (must specify if the Sponsor-Investigator developed the agent) When drug is not supplied: Agent X must be obtained from commercial sources. Example: Agent X must be obtained from commercial sources and is available in 500 mg/10 ampules and vials, and 1 gm/20 ml, 2.5 gm/50 ml, and 5 gm/100 ml vials. Consider including the following statement while reviewing the template: The cost of this agent will be the subject抯 responsibility. When drug is supplied: Study Agent X will be supplied for this study by Sponsor/company name. Packaging and labeling: Must specify the contents of the label if the Sponsor-Investigator developed the agent: name of drug, quantity of drug, date of packaging, recommended storage temp, lot number) Drug Accountability: To be included when drug is supplied The investigator or designated study personnel are responsible for maintaining accurate dispensing records of the study drug. All study drugs must be accounted for, including study drug accidentally or deliberately destroyed. Under no circumstances will the investigator allow the investigational drug to be used other than as directed by the protocol. If appropriate, drug storage, drug dispensing, and drug accountability may be delegated to the pharmacy section of the investigative site. Drug Destruction: To be included when drug is supplied This section should note the procedures for final reconciliation of the site抯 drug or device supply at the end of the study, and whether study drug or device is to be shipped back to a source or destroyed on site. If drug or device is to be shipped back to a source, note the address and contact information here. Suggested language: �365bet体育在线世界杯 the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and drug remaining. This reconciliation will be logged on the drug reconciliation form, signed and dated. Any discrepancies noted will be investigated, resolved, and documented prior to return or destruction of unused study drug. Drug destroyed on site will be documented in the study files.� Other Information: Include any other information, e.g., any special handling, any nursing implications, and any subject care implications. Note: if the protocol involves a placebo the sections listed above apply to all components of the protocol抯 treatment regimen (including placebo � if applicable) 10.0 CORRELATIVE STUDIES If this trial does not include correlative or special studies, this section should be marked 揘/A� and all instructions as well as the text below deleted. This section should be developed in close collaboration with the Translational Research and Pharmacology Core (TRPC) personnel at an early stage in protocol development. Please refer to guidance document for instructions. 10.1 Name of Correlative study #1 Describe the endpoint of correlative analysis #1. 10.1.1 Background Provide background describing the scientific basis for the correlative endpoint and its relevance to the objectives of the study. 10.1.2 Rationale for Analysis Describe how the analytical data will be analyzed and advance the objectives of the study. Consultation with Biostatistics is recommended for this section. 10.1.3 Collection of Specimens Include the number and specific type of specimens to be acquired from each subject, timepoints (cycles, day) and at what time. This information should also be included in the Study Calendar. You may also create a table that is correlative study procedure specific and add to this section. Please see Correlative study guidance document for exploratory study calendar examples. 10.1.4 Handling of Specimens Describe critical aspects of all processes involved in proper handling of the specimens. Include names and contact information (address, phone number, email, pager, etc.) of laboratories and/or individuals responsible for the acquisition, transportation, storage, tracking, processing, shipping and analyses of all specimens. Also include specific requirements for the handling of the specimens, including transport media, temperature, type of storage vessels (including type and volume of blood draw tubes, (e.g. heparin, EDTA, purple top, red top etc.), and maximal allowable time to complete processing or freezing. Please detail how the samples need to be shipped, when they need to be shipped, when to notify the lab of incoming shipment and any additional time restrictions. 10.1.5 Analytical Laboratory Will the specimens be analyzed at a clinical laboratory, a central reference laboratory, other collaborating laboratory, a Case Comprehensive Cancer Center Core Laboratory, or the Principal Investigator抯 laboratory? Please provide all contact information including the responsible party. 10.1.6 Methods Describe the methods used to measure the endpoint. Provide references or general information on the assay. Please state if a clinically validated assay (CLIA or CAP approved) will be used. In the event that there are more than one correlative/exploratory studies: Please repeat sections as follows, numbering appropriately: Instructions same as above. 10.2.1 Background 10.2.2 Rationale for Analysis 10.2.3 Collection of Specimens 10.2.4 Handling of Specimens 10.2.5 Analytical Laboratory 10.2.6 Methods 11.0 STUDY PARAMETERS AND CALENDAR Be aware of criteria prone to deviations. 11.1 Study Parameters Study parameters are used in conjunction with the study calendar. Please include these common criteria in study parameters: procedures that are not standard of care or are research procedures only, any extra labs or imaging studies that may need to be performed, any demographics or quality of life questionnaires that may be completed, all correlative study instructions. 11.1.1 Screening Evaluation Provide any necessary information that is not captured by the procedures in the study calendar here. Please see guidance document for specific examples. Please include any pre-RT planning in this section. 11.1.2 Treatment Period Provide any necessary information about each cycle/treatment visit that is not captured in the study calendar here. Please note if any procedures need to be completed within a certain timeframe. Be sure to include windows for fiducial placement, labs, visits, imaging, etc in order to avoid having to repeat tests, etc; e.g., labs +/- 3 days. 11.2 Calendar Please thoroughly review calendar guidance document. Consider a window of days, if appropriate for study. Indicate which components of the trial are appropriate for the window. The investigator should be cautious of tight windows (e.g., 24 hours) which may lead to many needless repeat tests or deviations and are almost never necessary. Examples: A visit window of +/- 3 days is allowed for labs (be specific: hematology and/or chemistries). A visit window of +/- 1 day is allowed for treatment. A visit window of +/- 7 days is allowed for 3 month follow-up visits. 12.0 MEASUREMENT OF EFFECT Please provide response criteria. If the criteria for solid tumors in the guidance document are not applicable, the investigator(s) should provide agent � or disease-appropriate criteria (e.g., for specific hematologic malignancies, supportive care agents, etc) with references. 13.0 DATA REPORTING / REGULATORY CONSIDERATIONS Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8.0 (Adverse Events: List and Reporting Requirements). 13.1 Data Reporting The OnCore� Database will be utilized, as required by the Case Comprehensive Cancer Center, to provide data collection for both accrual entry and trial data management. OnCore� is a Clinical Trials Management System housed on secure servers maintained at Case Western Reserve University. OnCore�. Access to data through OnCore� is restricted by user accounts and assigned roles. Once logged into the OnCore� system with a user ID and password, OnCore� defines roles for each user which limits access to appropriate data. User information and password can be obtained by contacting the OnCore� Administrator at OnCore-registration@case.edu. OnCore� is designed with the capability for study setup, activation, tracking, reporting, data monitoring and review, and eligibility verification.燭his study will utilize electronic Case Report Form completion in the OnCore� database. A calendar of events and required forms are available in OnCore�. 13.2 Regulatory Considerations The study will be conducted in compliance with ICH guidelines and with all applicable federal (including 21 CFR parts 56 & 50), state or local laws. 13.2.1 Written Informed consent Provision of written informed consent must be obtained prior to any study-related procedures. The Principal Investigator will ensure that the subject is given full and adequate oral and written information about the nature, purpose, possible risks and benefits of the study as well as the subject抯 financial responsibility. Subjects must also be notified that they are free to discontinue from the study at any time. The subject should be given the opportunity to ask questions and be allowed time to consider the information provided. The original, signed written Informed Consent Form must be kept with the Research Chart in conformance with the institution抯 standard operating procedures. A copy of the signed written Informed Consent Form must be given to the subject. Additionally, documentation of the consenting process should be located in the research chart. 13.2.2 Subject Data Protection In accordance with the Health Information Portability and Accountability Act (HIPAA), a subject must sign an authorization to release medical information to the sponsor and/or allow the sponsor, a regulatory authority, or Institutional Review Board access to subject抯 medical information that includes all hospital records relevant to the study, including subjects� medical history. 13.2.3 Retention of records The Principal Investigator of The Case Comprehensive Cancer Center supervises the retention of all documentation of adverse events, records of study drug receipt and dispensation, and all IRB correspondence for as long as needed to comply with local, national and international regulations. No records will be destroyed until the Principal Investigator confirms destruction is permitted. 13.2.4 Audits and inspections Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics Committee (IEC) or an Institutional Review Board (IRB) may visit the site to perform audits or inspections, including source data verification. The purpose of an audit or inspection is to systematically and independently examine all study-related activities and documents to determine whether these activities were conducted, and data were recorded, analysed, and accurately reported according to the protocol, Good Clinical Practice (GCP), guidelines of the International Conference on Harmonization (ICH), and any applicable regulatory requirements. For multi-center studies, participating sites must inform the sponsor-investigator of pending audits. 14.0 STATISTICAL CONSIDERATIONS Investigators must amend a protocol in order to capture additional data. Data can not be collected until the amendment has received IRB approval and will pertain only to data captured from that time period forward. This section should be developed in close collaboration with the study biostatistician: at an early stage in protocol development. SEE GUIDANCE DOCUMENT FOR REFERRALS The outline below is modified from CTEP protocol templates for standard Phase I and II studies (http://ctep.info.nih.gov/protocolDevelopment/default.htm#protocol_development), and is meant to provide a rough guideline as to what information should be included, recognizing that this will depend on the particular protocol and design used. Describe the study design. This includes: the objectives of the trials (primary, secondary and exploratory) the associated endpoint(s) please include time frames for completing associated endpoints the method of dose escalation (e.g. �3+3�; accelerated titration; continual reassessment method (CRM)). If the primary goal of the trial is to identify a maximum tolerated dose (or optimal biologic dose, or both) provide a precise definition of it or reference the appropriate protocol section. If the trial is randomized indicate the proportion of subjects to be accrued to each dose level (e.g. equal randomization). Provide a statistical justification for the number of subjects to be enrolled based on the primary goal(s) of the trial. If correlative studies are being performed address the suitability of the proposed sample size to obtain meaningful results (even if the goal of such studies is hypothesis generating). Also include the objectives, endpoints, and any methods not described in correlative research section of the protocol. Describe how the primary and secondary/correlative endpoints will be analyzed (e.g. parametric versus non-parametric methods; one versus two-sided statistical tests; the confidence limits that will be used for estimation). If correlative studies are included, address whether or not adjustments to p-values will be made for multiple comparisons; and if appropriate the method to be used. Provide an estimate of the accrual rate. REFERENCES Please provide the citations for all publications referenced in the text. Publications should be organized as any standard bibliography using AMA style formatting as presented below. Number. Last name followed by initial of first name. Title of article in sentence format. Title of Journal in Abbreviated Title Format. Month Year published;edition or volume:page-page. Example: Hensen, DE, Albores-Savvedra J, Corle D. Carcinoma of the gallbladder, histologic types, stage of disease and survival rates. Cancer 1992;70:1493-1497. APPENDIX I PERFORMANCE STATUS CRITERIA ECOG Performance Status ScaleKarnofsky Performance ScaleGradeDescriptionPercentDescription 0 Normal activity. Full active, able to carry on all pre-disease performance without restriction.  100 Normal, no complaints, no evidence of disease. 90Able to carry on normal activity; minor signs or symptoms of disease. 1Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work). 80Normal activity with effort; some signs or symptoms of disease. 70Cares for self, unable to carry on normal activity or to do active work.  2In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% if waking hours. 60Requires occasional assistance, but is able to care for most of his/her needs. 50Requires considerable assistance and frequent medical care. 3In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 40 Disabled, requires special care and assistance. 30 Severely disabled, hospitalization indicated. Death not imminent. 4100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 20Very sick, hospitalization indicated. Death not imminent.  10Moribund, fatal processes progressing rapidly.5Dead.0Dead APPENDIX II SUBJECT PILL DIARY Revise the areas in red to fit the protocol. Delete #2 under instructions and the second column of pills if only one mg or one agent is used. Add additional columns and rows as needed for multiple agents/longer cycles. Subject Name ________________________Protocol #________________ Subject Study ID __________ Cycle #: _______ Month #: _______ INSTRUCTIONS FOR THE SUBJECT: 1. You will take  FORMTEXT # of  tablets of  FORMTEXT ____ mg  FORMTEXT record agent pills each day. Take the tablets [on an empty stomach / with a full glass (8 ox) of water / before or 2 hours after meals / with or without food, as you wish]. 2. You will take  FORMTEXT # of  tablets of  FORMTEXT ____ mg  FORMTEXT record agent pills each day. Take the tablets [on an empty stomach / with a full glass (8 ox) of water / before or 2 hours after meals / with or without food, as you wish]. 3. Record the date, the number of tablets you took, and what time you took them. 4. If you have any comments please record them in the 揅omments� column below. 5. Please bring your pill bottle and this form to your physician when you come for your next appointment. 6. Please sign your name at the bottom of the diary.DateDay# of  FORMTEXT _____ mg  FORMTEXT record agent pills and time taken # of  FORMTEXT _____ mg  FORMTEXT record agent pills and time takenComments12345678910111213141516171819202122232425262728Add/remove days as neededSubject抯 Signature: ________________________________________ Date: ___________ APPENDIX III SUBJECT PILL DIARY FOR TWICE DAILY DOSING Add or delete columns and rows and revise the information in red as appropriate for the trial. Subject Name ______________________ Subject Study ID __________ Today抯 date ___/___/___ Drug _____________________________ Cycle #:_______________________________ INSTRUCTIONS FOR THE SUBJECT: 1. Complete one form every 4 weeks (one treatment cycle). 2. You will take  FORMTEXT record agent tablets twice each day about 12 hours apart. Take the tablets [on an empty stomach / with a full glass (8 ox) of water / before or 2 hours after meals / with or without food, as you wish]. Morning dose: take  FORMTEXT # of   FORMTEXT ____ mg tablet(s) [if applicable, and  FORMTEXT # of   FORMTEXT ____ mg tablet(s)] Evening dose: take  FORMTEXT # of   FORMTEXT ____ mg tablet(s), [if applicable, and  FORMTEXT # of   FORMTEXT ____ mg tablet(s)] 3. Record the date, the number of tablets of each size that you took, and what time you took them. 4. If you have any comments or notice any side effects, please record them in the 揅omments� column. 5. 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� ���� �FMicrosoft Office Word Document MSWordDocWord.Document.8�9瞦 � ���� �FMicrosoft Office Word Document MSWordDocWord.Document.8�9瞦ObjInfo ����WordDocument�������������.SummaryInformation( �����DocumentSummaryInformation8�������������欹�` ��l bjbj鎳鎳 .勴勴l�������$� � � � � ,$酠�00000   `MbMbMbMbMbMbM$種hQb哅<  <<哅00�汳   < 00`M <`M   0$ 08`�� F 訪�盡0酠 丵\�丵 丵 �; "- EY�   哅哅   酠<<<<$$$� �$$$ $$$���� APPENDIX [record letter] NEW YORK HEART ASSOCIATION (NYHA) CARDIAC CLASSIFICATION The NYHA classification system relates symptoms to everyday activities and the patient抯 quality of life. ClassSymptoms Class I (Mild)  No limitation of physical activity. Ordinary physical activity does not cause fatigue, palpitation, or dyspnea (shortness of breath).  Class II (Mild) Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea.  Class III (Moderate) Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea.  Class IV (Severe) Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency at rest. If any physical activity is undertaken, discomfort is increased.   RSUWs������������h i j k m | } ~  ! 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