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11.0 adverse events 11.1 experimental

The study intervention, atorvastatin calcium, is a standard drug and dose commercially available for primary and secondary prevention of cardiovascular disease. Atorvastatin has a widely accepted tolerability profile with few serious side effects [6]. A list of adverse events (AEs) that have occurred or might occur (Reported Adverse Events and Potential Risks) can be found in Section 6.2, Pharmaceutical Information, as well as the Investigator Brochure or package insert.
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11.2 adverse event monitoring

Adverse event data collection and reporting, which are required as part of every clinical trial, are done to ensure the safety of Subjects enrolled in the studies as well as those who will enroll in future studies using similar agents. Adverse events are reported in a routine manner at scheduled times during a trial. Additionally, certain adverse events must be reported in an expedited manner to allow for optimal monitoring of patient safety and care.  
AEs will be collected throughout the study period and at follow-up time points. Grade 1 and 2 laboratory abnormalities/AEs will not be collected, with the exception of AST or ALT > 3x the upper limit of normal, which are known AEs related to statin use and indicate that a participant must be evaluated for possible discontinuation of the study agent. Only lab abnormalities graded 3 or above and that are considered at least *possibly* **related to the**
study agent will be collected and reported. **All serious adverse events (SAEs) will continue to be collected,** regardless of attribution.
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11.3 definitions

All patients experiencing an adverse event, considered at least *possibly* **related to the study drug with the**
exception of grade 1 and 2 laboratory abnormalities, will be monitored until:
➢ **the adverse event resolves or the symptoms or signs that constitute the adverse event return to baseline;** ➢ **any abnormal laboratory values have returned to baseline;** ➢ **there is a satisfactory explanation other than the study drug for the changes observed; or** ➢ **death.**
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11.3.1 definition of adverse event

An adverse event (AE) is any untoward medical occurrence in a patient receiving study treatment and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an experimental intervention, whether or not related to the intervention.
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11.3.2 severity of adverse events

All non-hematologic adverse events will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The CTCAE provides descriptive terminology and a grading scale for each adverse event listed. The CTCAE v4 is available at http://ctep.cancer.gov/reporting/ctc.html.  
If no CTCAE grading is available, the severity of an AE is graded as follows:
Mild (grade 1): the event causes discomfort without disruption of normal daily activities.  
Moderate (grade 2): the event causes discomfort that affects normal daily activities. Severe (grade 3): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Life-threatening (grade 4): the patient was at risk of death at the time of the event. Fatal (grade 5): the event caused death.
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11.3.3 serious adverse events

A "serious" adverse event is defined in regulatory terminol**ogy as any untoward medical occurrence that:**  
11.3.3.1 **Results in death. If death results from (progression of) the disease, the disease should be reported as a**
serious adverse event (SAE) itself.
11.3.3.2 **Is life-threatening (the patient was at risk of death at the time of the event; it does not refer to an event**
that hypothetically might have caused death if it were more severe).  
11.3.3.3 Requires in-**patient hospitalization or prolongation of existing hospitalization for ≥ 24 hours.**
11.3.3.4 **Results in persistent or significant disability or incapacity.** 11.3.3.5 **Is a congenital anomaly/birth defect.**  
11.3.3.6 **Is an important medical event. Any event that does not meet the above criteria, but that in the judgment**
of the investigator jeopardizes the patient, may be considered for reporting as a serious adverse event. The event may require medical or surgical intervention to prevent one of the outcomes listed in the definition of "Serious Adverse Event." For example: allergic bronchospasm requiring intensive treatment in an emergency room or at home; convulsions that may not result in hospitalization; development of drug abuse or drug dependency.
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11.4 steps to determine if

Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria for Adverse Events (CTCAE v4). Step 2: Grade the adverse event using the NCI CTCAE v4.  
Step 3: Determine whether the adverse event is related to the protocol therapy Attribution categories are as follows:  
- Definite - The AE *is clearly related* **to the study treatment.**
- Probable - The AE *is likely related* **to the study treatment.**
- Possible - The AE *may be related* **to the study treatment.**
- Unlikely - The AE *is doubtfully related* **to the study treatment.**
- Unrelated - The AE *is clearly NOT related* **to the study treatment.**
Note: This includes all events that occur within 30 days of the last dose of protocol treatment. Any event that occurs more than 30 days after the last dose of treatment and is attributed (possibly, probably, or definitely) to the agent(s) must also be reported accordingly.  
Step 4: Determine the prior experience of the adverse event. Expected events are those that have been previously identified as resulting from administration of the agent. An adverse event is considered unexpected, for expedited reporting purposes only, when either the type of event or the severity of the event is not listed in:
- **the current known adverse events listed in the Agent Information Section of this protocol;**
- **the drug package insert;**
- **the current Investigator's Brochure**
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11.5 reporting requirements for adverse

- **The Principal Investigator must be notified within 24 hours of learning of any serious adverse events,**
regardless of attribution, occurring during the study or within 30 days of the last administration of the study drug.  
- **The CSMC IRB must be notified no later than 10 business days after the investigator becomes aware**
of the event or receives an external report of "any unanticipated problems involving risk to subjects or others" (UPR/UPIRSO). The following events meet the definition of UPR:
1. **Any serious event (injuries, side effects, deaths, or other problems), which in the opinion of the**
Principal Investigator was unanticipated, involved risk to subjects or others, and was possibly related to the research procedures.  
2. **Any serious accidental or unintentional change to the IRB-approved protocol that alters the level**
of risk.  
3. **Any deviation from the protocol taken without prior IRB review to eliminate apparent immediate**
hazard to a research subject.  
4. **Any new information (e.g., publication, safety monitoring report, updated sponsor safety report),**
interim result, or other finding that indicates an unexpected change to the risk/benefit ratio for the research.  
5. **Any breach in confidentiality that may involve risk to the subject or others.** 6. **Any complaint of a subject that indicates an unanticipated risk or that cannot be resolved by the**
Principal Investigator.
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11.5.2 routine reporting

All other adverse events - **such as those that are expected, or are unlikely or definitely not related to the study** participation - **are to be reported annually as part of regular data submission.**
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11.6 stopping rules

There are no formal stopping rules. The study agent, atorvastatin calcium, is a commonly prescribed drug indicated for long-term use**. The study agent will be stopped in the event of an AE ≥ grade 3 considered possibly,** probably, or definitely related to the study agent. The study agent will be restarted after resolution unless the subject experiences grade 3 or greater myopathy (unexplained muscle symptoms and **CPK > 5 times ULN) or**
persistent hepatotoxicity (ALT or AST > 3 times ULN) that is considered possibly, probably, or definitely related to the study agent, in which case the study agent will be permanently discontinued.
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12.0 study management 12.1 conflict

All investigators will follow the Cedars Sinai Medical Center conflict of interest policy. There are no conflicts of interest to report.
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12.2 institutional review board (irb)

It is expected that the IRB will have the proper representation and function in accordance with federally mandated regulations. The IRB should approve the consent form and protocol.  
In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to ethical principles that have their origin in the Declaration of Helsinki.  
Before recruitment and enrollment onto this study, the patient will be given a full explanation of the study and will be given the opportunity to review the consent form. Each consent form must include all the relevant elements currently required by the FDA Regulations and local or state regulations. Once this essential information has been provided to the patient and the investigator is assured that the patient understands the implications of participating in the study, the patient will be asked to give consent to participate in the study by signing an IRB approved consent form. Prior to a **patient's participation in the trial, the written informed consent form should be signed and personally**
dated by the patient and by the person who conducted the informed consent discussion.
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12.3 registration procedures

All subjects that sign informed consent will be assigned a subject number sequentially by their date of consent. Those subjects that do not pass the screening phase will be listed as screen failures on the master list of consented subjects. Eligible subjects, as determined by screening procedures and verified by a treating investigator, will be registered on study at Cedars Sinai Medical Center by the Study Coordinator.  
Issues that would cause treatment delays after registration should be discussed with the Principal Investigator (PI). I**f a patient does not receive protocol therapy following registration, the patient's registration on the study may be**
canceled. The Study Coordinator should be notified of cancellations as soon as possible.  
The study team will track all subjects who sign consent on a subject screening/enrollment log using a unique screening ID (S01, S02, etc.). Subjects found to be ineligible will be recorded as screen failures. Subjects found to be eligible will be registered.
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12.3.1 eligibility verification

Prior to registration, all subjects must undergo eligibility verification by the SOCCI Clinical Research Office (CRO). The following documents will be completed and provided for review:  
- **Registration form (or equivalent)** - **Copy of required laboratory tests**
- **Copy of required imaging reports**
- **Eligibility checklist (signed by investigator)**
- **Signed patient consent form and Subject's Bill of Rights** - **HIPAA authorization form**
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12.3.2 registration

After eligibility is verified, registration is completed as follows:  
- **Assign a patient study number** - **Assign the patient a dose as determined through communication with Biostatistics and the principal**
investigator
- **Enter the patient in OnCore** - **Notify the investigational pharmacy and treating physicians that a subject has gone on study and**
anticipated treatment start date
Oversight by the principal investigator is required throughout the entire registration process.
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12.4 record keeping and data

Data storage and tracking systems will be developed using the Research Electronic Data Capture (REDCap)
application, stored and maintained on a secure CSMC Enterprise Information Systems (EIS) server. REDCap is a web-based application that is HIPAA compliant (secure location, automatic encryption, authentication, authorization, and audit trail) and is only accessed via password. Appropriate administrative, physical, and technical safeguards are in place to ensure the confidentiality, integrity, and security of electronic protected health information (EPHI). Security measures for the databases include password management, transmission security, and data encryption to guard against unauthorized access to EPHI while it is being transmitted over the network. Only certified research personnel who are listed on the approved IRB application will be given access to the data. Questionnaire data will be entered into the REDCap database. The data will be checked for missing data and reviewed for accuracy by clinical research staff. Programs will be developed to prevent data entry errors and to perform extensive data edits, including checks for inconsistences and permissible variable values. A data dictionary will document all database activities, and contain detailed information about each database variable. A secure OnCore database will be developed to track the storage locations and status of study biospecimens.
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12.5 data and safety monitoring

A Data Safety Monitoring Board (DSMB) will be convened and will meet every six months to review data relating to safety and efficacy, to conduct and review interim analyses, and to ensure the continued scientific validity and merit of the study, according to the SOCCI DSMB Charter. There will be interim reviews conducted by the DSMB for the purpose of monitoring study conduct and assessing subject safety. The interim reviews will include review of all monitoring and audit reports; serious adverse events (SAEs) that occur; and protocol deviations and exceptions. The DSMB findings and any concerns and recommendations will be reported in writing to the Principal Investigator. A summary report will be forwarded by the Principal Investigator or his/her designee to the Cedars-Sinai Medical Center IRB.
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12.6 executive committee and internal

The project investigators with the assistance of the study coordinator will have day-to-day responsibility for the trial. They will ensure that recruitment and scientific goals are met according to the milestone schedule. The Executive Committee, including Drs. Goodman, Wei, Mita, and Bairey Merz; and Ms. Travis-Teague, will have monthly teleconferences and quarterly in-person meetings. Meeting agendas will include the following content areas: a) Present and review data obtained and evaluate progress toward achieving recruitment and follow-up goals; b) Identify and resolve all impediments to the successful implementation and completion of the project; c) Review and discuss interim data to assist in planning the remaining work; d) Discuss, coordinate, and delegate presentations to community and advocacy groups regarding the growing importance of cardioprotection among women with breast cancer; e) Promote enthusiasm and maintain the momentum of the project.
An IAB will review the study and assist the investigators in protocol development, problem solving, evaluating scientific progress, identifying research opportunities, and guiding future research planning. The IAB will meet annually with the Executive Committee, although each IAB member will be available for consultation and advice on an ad hoc basis. The composition of the IAB includes Dr. Armando Giuliano, Co-director of the Brandman Breast Center, a breast surgeon who promulgated the practice of the sentinel node biopsy and a recent recipient of the Susan Komen Brinker Award for Scientific Distinction in Clinical Research, their highest award for clinical research; Dr. Beth Karlan, an oncologist and Director of the Women's Cancer Program who sits on the National Cancer Advisory Board; Dr. Debiao Li, Director of the Biomedical Imaging Research Institute and President of the International Society for Magnetic Resonance in Medicine; and Dr. Steven Piantadosi, immediate past Director of the Samuel Oschin Comprehensive Cancer Institute and one of the world's leading experts in the design and analysis of clinical trials for cancer research. Following the end of the meeting, the IAB will prepare a written report to the Executive Committee.
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12.7 adherence to the protocol

Adherence to the protocol, Good Clinical Practice (GCP) and institutional policy will be monitored by the PI
during the course of the study through routine Disease Research Group (DRG) meetings (or equivalent). In addition, the SOCCI CRO Quality Management Core (QMC) will conduct the following:
1) Audit preparations (AP) prior to audit conducted by any external auditing agency (i.e., NCI or FDA). The purpose of an AP is to ensure adequate source documentation to support protocol compliance and data integrity are present and organized, and to identify and correct any major findings prior to the external audit, if possible.  
2) A thorough review of selected subject cases, regulatory files, and Investigational Product (IP)
accountability records (if applicable) within 2-3 months after the first subject is enrolled and annually thereafter while subjects are receiving investigational intervention. Reviews will include a representation of cases, pharmacy, and regulatory files from external sites.  
3) Central eligibility verification for all subjects enrolled as described in protocol section 12.3.1 Eligibility Verification.  
4) Central review of all eligibility waivers and exception requests by a SOCCI Medical reviewer to assess appropriateness and risk to ensure quality data and ensure subject safety protections for investigator initiated research.  
5) For multi-site studies, a central review of subject registration and eligibility verification.
For any protocol, the QMC has the authority to request more frequent reviews or closer safety monitoring if it is deemed appropriate for any reason. Additionally, to monitor data quality and protocol compliance once all subjects have discontinued intervention, decreased monitoring may be implemented.  
Except for an emergency situation in which proper care for the protection, safety, and well-being of the study patient requires alternative treatment, the study shall be conducted exactly as described in the approved protocol. For any such emergency modification implemented, an IRB modification form must be completed within five (5) business days of making the change.
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12.8 amendments to the protocol

Should amendments to the protocol be required, the amendments will be originated and documented by the Principal Investigator. It should also be noted that when an amendment to the protocol substantially alters the study design or the potential risk to the patient, a revised consent form might be required. The written amendment, and if required the amended consent form, must be sent to the IRB for approval prior to implementation.
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12.9 record retention

Study documentation includes all Case Report Forms, data correction forms or queries, source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient consent forms). Source documents include all recordings of observations or notations of clinical activities and all reports and records necessary for the evaluation and reconstruction of the clinical research study. Government agency regulations and directives require that the study investigator must retain all study documentation pertaining to the conduct of a clinical trial. In the case of a study with a drug seeking regulatory approval and marketing, these documents shall be retained for at least two years after the last approval of marketing application in an International Conference on Harmonization (ICH) region. In all other cases, study documents should be kept on file until three years after the completion and final study report of this investigational study.
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12.10 obligations of investigators

The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal Investigator is responsible for personally overseeing the treatment of all study patients. The Principal Investigator must assure that all study site personnel, including sub-investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after study completion. The Principal Investigator at each institution or site will be responsible for assuring that all the required data will be collected and entered onto the Case Report Forms. Periodically, monitoring visits will be conducted and the Principal Investigator will provide access to his/her original records to permit verification of proper entry of data.  
At the completion of the study, all case report forms will be reviewed by the Principal Investigator and will require his/her final signature to verify the accuracy of the data.
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56. Negishi K, Negishi T, Hare JL, Haluska BA, Plana JC, Marwick TH. Independent and incremental value of deformation indices for prediction of trastuzumab-induced cardiotoxicity. J Am Soc Echocardiogr 2013;26(5):493-8.  
57. Ho E, Brown A, Barrett P, Morgan RB, King G *et al.* **Subclinical anthracycline- and trastuzumab-induced**
cardiotoxicity in the long-term follow-up of asymptomatic breast cancer survivors: a speckle tracking echocardiographic study. Heart 2010;96(9):701-7.  
58. Cho GY, Marwick TH, Kim HS, Kim MK, Hong KS, Oh DJ. Global 2-dimensional strain as a new prognosticator in patients with heart failure. J Am Coll Cardiol 2009;54(7):618-24.  
59. Sawaya H, Plana JC, Scherrer-Crosbie M. Newest echocardiographic techniques for the detection of cardiotoxicity and heart failure during chemotherapy. Heart Fail Clin 2011;7(3):313-21.  
60. Rosen BD, Edvardsen T, Lai S, Castillo E, Pan L *et al.* **Left ventricular concentric remodeling is**
associated with decreased global and regional systolic function: the Multi-Ethnic Study of Atherosclerosis. Circulation 2005;112(7):984-91.  
61. Choi EY, Rosen BD, Fernandes VR, Yan RT, Yoneyama K *et al.* **Prognostic value of myocardial**
circumferential strain for incident heart failure and cardiovascular events in asymptomatic individuals: the Multi-Ethnic Study of Atherosclerosis. Eur Heart J 2013;34(30):2354-61.  
62. Hor KN, Wansapura J, Markham LW, Mazur W, Cripe LH *et al.* **Circumferential strain analysis identifies**
strata of cardiomyopathy in Duchenne muscular dystrophy: a cardiac magnetic resonance tagging study. J Am Coll Cardiol 2009;53(14):1204-10.  
63. Mordi I, Bezerra H, Carrick D, Tzemos N. The Combined Incremental Prognostic Value of LVEF, Late Gadolinium Enhancement, and Global Circumferential Strain Assessed by CMR. JACC Cardiovasc Imaging 2015;8(5):540-9.  
64. Saito M, Negishi K, Eskandari M, Huynh Q, Hawson J *et al.* **Association of left ventricular strain with**
30-day mortality and readmission in patients with heart failure. J Am Soc Echocardiogr 2015;28(6):65266.  
65. Agarwal M, Shufelt C, Mehta PK, Gill E, Berman DS *et al.* **Cardiac risk factors and myocardial perfusion**
reserve in women with microvascular coronary dysfunction. Cardiovasc Diagn Ther 2013;3(3):146-52.  
66. Shufelt CL, Thomson LE, Goykhman P, Agarwal M, Mehta PK *et al.* **Cardiac magnetic resonance**
imaging myocardial perfusion reserve index assessment in women with microvascular coronary dysfunction and reference controls. Cardiovasc Diagn Ther 2013;3(3):153-60.  
67. Goykhman P, Mehta PK, Minissian M, Thomson LE, Berman DS *et al.* **Subendocardial ischemia and**
myocarditis in systemic lupus erythematosus detected by cardiac magnetic resonance imaging. J Rheumatol 2012;39(2):448-50.  
68. Nelson MD, Szczepaniak LS, Wei J, Haftabaradaren A, Bharadwaj M *et al.* **Diastolic dysfunction in**
women with signs and symptoms of ischemia in the absence of obstructive coronary artery disease: a hypothesis-generating study. Circ Cardiovasc Imaging 2014;7(3):510-6.  
69. Dall'Armellina E, Piechnik SK, Ferreira VM, Si QL, Robson MD *et al.* **Cardiovascular magnetic**
resonance by non contrast T1-mapping allows assessment of severity of injury in acute myocardial infarction. J Cardiovasc Magn Reson 2012;14:15.  
70. de Meester de Ravenstein C, Bouzin C, Lazam S, Boulif J, Amzulescu M *et al.* **Histological Validation of**
measurement of diffuse interstitial myocardial fibrosis by myocardial extravascular volume fraction from Modified Look-Locker imaging (MOLLI) T1 mapping at 3 T. J Cardiovasc Magn Reson 2015;17:48.  
71. Sharif B, Dharmakumar R, LaBounty T, Arsanjani R, Shufelt C *et al.* **Towards elimination of the darkrim artifact in first-pass myocardial perfusion MRI: removing Gibbs ringing effects using optimized**
radial imaging. Magn Reson Med 2014;72(1):124-36.  
72. Broussard JL, Nelson MD, Kolka CM, Bediako IA, Paszkiewicz RL *et al.* **Rapid development of cardiac**
dysfunction in a canine model of insulin resistance and moderate obesity. Diabetologia 2016;59(1):197207.  
73. Nelson MD, Szczepaniak LS, LaBounty TM, Szczepaniak E, Li D *et al.* **Cardiac steatosis and left**
ventricular dysfunction in HIV-infected patients treated with highly active antiretroviral therapy. JACC Cardiovasc Imaging 2014;7(11):1175-7.  
74. Nelson MD, Haykowsky MJ, Petersen SR, DeLorey DS, Stickland MK *et al.* **Aerobic fitness does not**
influence the biventricular response to whole body passive heat stress. J Appl Physiol (1985) 2010;109(5):1545-51.  
75. Nelson MD, Haykowsky MJ, Petersen SR, DeLorey DS, Cheng-Baron J, Thompson RB. Increased left ventricular twist, untwisting rates, and suction maintain global diastolic function during passive heat stress in humans. Am J Physiol Heart Circ Physiol 2010;298(3):H930-7.  
76. Nelson MD, Altamirano-Diaz LA, Petersen SR, DeLorey DS, Stickland MK *et al.* **Left ventricular**
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77. Schmitz KH, Prosnitz RG, Schwartz AL, Carver JR. Prospective surveillance and management of cardiac toxicity and health in breast cancer survivors. Cancer 2012;118(8 Suppl):2270-6.  
78. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A *et al.* **The European Organization for**
Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85(5):365-76.  
79. Sprangers MA, Groenvold M, Arraras JI, Franklin J, te Velde A *et al.* **The European Organization for**
Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: first results from a three-country field study. J Clin Oncol 1996;14(10):2756-68.  
80. Letellier ME, Dawes D, Mayo N. Content verification of the EORTC QLQ-C30/EORTC QLQ-BR23 with the International Classification of Functioning, Disability and Health. Qual Life Res 2015;24(3):75768.  
81. Maji D, Shaikh S, Solanki D, Gaurav K. Safety of statins. Indian J Endocrinol Metab 2013;17(4):636-46. 82. Coelho-Filho OR, Rickers C, Kwong RY, Jerosch-Herold M. MR myocardial perfusion imaging.  
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83. Messroghli DR, Nordmeyer S, Dietrich T, Dirsch O, Kaschina E *et al.* **Assessment of diffuse myocardial**
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84. Schelbert EB, Testa SM, Meier CG, Ceyrolles WJ, Levenson JE *et al.* **Myocardial extravascular**
extracellular volume fraction measurement by gadolinium cardiovascular magnetic resonance in humans:
slow infusion versus bolus. J Cardiovasc Magn Reson 2011;13:16.  
85. Ugander M, Oki AJ, Hsu LY, Kellman P, Greiser A *et al.* **Extracellular volume imaging by magnetic**
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86. Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 1975;31(1):103-15.  
87. Mavinkurve-Groothuis AM, Marcus KA, Pourier M, Loonen J, Feuth T *et al.* **Myocardial 2D strain**
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88. Rubin DB. Inference and missing data. Biometrika 1976;63(3):581-592. 89. Little RJA, Rubin DB. Statistical Analysis with Missing Data. Second Edition. John Wiley & Sons: New York, 2002.
study schema
appendix a

| ECOG Performance Status Scale                                                                                                                                                            | Karnofsky Performance Scale                                                                       |                                                                                 |                                                                        |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------|------------------------------------------------------------------------|
| Grade                                                                                                                                                                                    | Descriptions                                                                                      | Percent                                                                         | Description                                                            |
| 100                                                                                                                                                                                      | Normal, no complaints, no evidence  of disease.                                                   |                                                                                 |                                                                        |
| 0                                                                                                                                                                                        | Normal activity. Fully active, able to carry on  all pre-disease performance without restriction. | 90                                                                              | Able to carry on normal activity;  minor signs or symptoms of disease. |
| 80                                                                                                                                                                                       | Normal activity with effort; some  signs or symptoms of disease.                                  |                                                                                 |                                                                        |
| Symptoms, 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). |                                                                                                   |                                                                                 |                                                                        |
| 1                                                                                                                                                                                        | 70                                                                                                | Cares for self, unable to carry on  normal activity or to do active work.       |                                                                        |
| In 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% of waking hours.                           | 60                                                                                                | Requires occasional assistance, but is  able to care for most of his/her needs. |                                                                        |
| 2                                                                                                                                                                                        | 50                                                                                                | Requires considerable assistance and  frequent medical care.                    |                                                                        |
| 40                                                                                                                                                                                       | Disabled, requires special care and  assistance.                                                  |                                                                                 |                                                                        |
| In bed > 50% of the time. Capable of only                                                                                                                                                |                                                                                                   |                                                                                 |                                                                        |
| 3                                                                                                                                                                                        | limited self-care, confined to bed or chair more  than 50% of waking hours.                       | 30                                                                              | Severely disabled, hospitalization  indicated. Death not imminent.     |
| 20                                                                                                                                                                                       | Very sick, hospitalization indicated.  Death not imminent.                                        |                                                                                 |                                                                        |
| 100% bedridden. Completely disabled. Cannot                                                                                                                                              |                                                                                                   |                                                                                 |                                                                        |
| 4                                                                                                                                                                                        | carry on any self-care. Totally confined to bed  or chair.                                        | 10                                                                              | Moribund, fatal processes progressing  rapidly.                        |
| 5                                                                                                                                                                                        | Dead                                                                                              | 0                                                                               | Dead                                                                   |  
Performance Status Criteria
study schema
appendix b study diary

Please bring your completed diary and your study drug supply, including empty bottles, to every study visit.  
This will help us keep track of your study drug and how well you are tolerating it.
study schema
participant study id participant name

Visit 1 (Baseline) - Visit 2 (Month 1) Visit 2 (Month 1) - **Visit 3 (Month 3)**
Visit 3 (Month 3) - Visit 4 (Month 6) Visit 4 (Month 6) - **Visit 5 (Month 9)** Visit 5 (Month 9) - **Visit 6 (Month 12)**  
Instructions  
Complete one line in the table for each day you take the study drug.  
Please contact the study research staff at «staff phone number» if you have any questions.  
- **Take your study drug once per day at bedtime or with an evening meal. Please swallow the capsule whole**  
and do not chew, crush, or open it. Take the capsule at the same time every day.  
- **Record the date and time of day you took the study drug.** - **If you miss a dose of the study drug, take it as soon as you remember. Do not take the drug if it has been**  
more than 12 hours since you missed your last dose. Wait and take the next dose at your regular time. Do not take two doses of the study drug at the same time.  
- **If you notice any side effects such as joint pain, mild muscle aches, diarrhea, nausea, respiratory infection,**  
painful or difficult urination, pain in feet, ankles, hands, or wrists, or if you have any other symptoms,  
please write them in the Comments column and report them to the study staff when they call you.  
Day Date Time Study Drug Taken Check if Dose Missed Comments  
1 **____:____ a.m. / p.m. Dose not taken today**  
| please write them in the Comments column and report them to the study staff when they call you.   |           |                       |                      |                      |
|---------------------------------------------------------------------------------------------------|-----------|-----------------------|----------------------|----------------------|
| Day                                                                                               | Date      | Time Study Drug Taken | Check if Dose Missed | Comments             |
| 1                                                                                                 | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 2                                                                                                 | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 3                                                                                                 | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 4                                                                                                 | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 5                                                                                                 | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 6                                                                                                 | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 7                                                                                                 | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 8                                                                                                 | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 9                                                                                                 | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 10                                                                                                | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 11                                                                                                | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 12                                                                                                | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 13                                                                                                | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 14                                                                                                | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 15                                                                                                | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 16                                                                                                | ____:____ | a.m. /                | p.m.                 | Dose not taken today |  
| Protocol Version 3.1, November 29, 2017   |           |                       |                      |                      |
|-------------------------------------------|-----------|-----------------------|----------------------|----------------------|
| Day                                       | Date      | Time Study Drug Taken | Check if Dose Missed | Comments             |
| 17                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 18                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 19                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 20                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 21                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 22                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 23                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 24                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 25                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 26                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 27                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 28                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 29                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 30                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 31                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 32                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 33                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 34                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 35                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 36                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 37                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 38                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 39                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 40                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 41                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 42                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 43                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 44                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 45                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 46                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 47                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 48                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 49                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 50                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |  
| Protocol Version 3.1, November 29, 2017   |           |                       |                      |                      |
|-------------------------------------------|-----------|-----------------------|----------------------|----------------------|
| Day                                       | Date      | Time Study Drug Taken | Check if Dose Missed | Comments             |
| 51                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 52                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 53                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 54                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 55                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 56                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 57                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 58                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 59                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 60                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 61                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 62                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 63                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 64                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 65                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 66                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 67                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 68                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 69                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 70                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 71                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 72                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 73                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 74                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 75                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 76                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 77                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 78                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 79                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 80                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 81                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |
| 82                                        | ____:____ | a.m. /                | p.m.                 | Dose not taken today |  
| Protocol Version 3.1, November 29, 2017                                  |                                    |                       |                      |                      |
|--------------------------------------------------------------------------|------------------------------------|-----------------------|----------------------|----------------------|
| Day                                                                      | Date                               | Time Study Drug Taken | Check if Dose Missed | Comments             |
| 83                                                                       | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 84                                                                       | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 85                                                                       | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 86                                                                       | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 87                                                                       | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 88                                                                       | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 89                                                                       | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 90                                                                       | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 91                                                                       | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 92                                                                       | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 93                                                                       | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 94                                                                       | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 95                                                                       | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 96                                                                       | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 97                                                                       | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 98                                                                       | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 99                                                                       | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 100                                                                      | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 101                                                                      | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 102                                                                      | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 103                                                                      | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
| 104                                                                      | ____:____                          | a.m. /                | p.m.                 | Dose not taken today |
|                                                                          | FOR STUDY TEAM USE ONLY            | Staff Initials:       |                      |                      |
| Date study drug dispensed:                                               | Date study drug returned:          |                       |                      |                      |
| Number of pills/capsules dispensed:                                      | Number of pills/capsules returned: |                       |                      |                      |
| Number of pills/capsules that should have been taken:  Discrepancy/notes |                                    |                       |                      |                      |