1. Safety Reporting
Nichol McBee, MPH, CCRP

2. Adverse Event: Definition
Untoward medical occurrence that occurs during the protocol reporting period, regardless of whether it is considered related to the test article
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, disease, syndrome, or intercurrent illness in a subject who receives test article (or was intended to receive test article) that emerges during test article administration or is a preexisting condition that worsens relative to the pretreatment state, and that does not necessarily have a causal relationship to this treatment.
Please note that an unchanged, chronic conditions should not be recorded as an adverse event unless there is an exacerbation of the chronic condition.

3. Unexpected Adverse Drug Reaction
Not pre-specified as an expected event in the protocol
Not previously reported in the CLEAR patient population
An unexpected adverse drug reaction is defined as an event that is not pre-specified as an expected event in the protocol and has not previously been reported in the CLEAR patient population.

4. Intensity Grading Grades 1 - 5 1 (mild) to 5 (death)
Grades are event specific
Adverse events will be graded generally as grades 1 through 5 with 1 being mild and 5 being death.
The grades are event specific. Some events will have all 5 grades available whereas other events will only have some of the grades available. The EDC will only show the grades available for each event. It is highly recommended that you enter adverse events directly into the EDC as they happen to accurately grade each event.

5. Causality Not related Possibly related Probably related
Definitely related
An adverse event can be classified as not related, possibly related, probably related, or definitely related to the test article.
Unrelated: There is evidence that the adverse event definitely has an etiology other than the test article. AEs with onset more than 72 hours post test article administration are not expected to be related to the test article.
Possibly Related: The adverse event has a temporal and/or biological relationship to test article administration. However, an alternative etiology may be responsible for the adverse event.
Probably Related: The adverse event has a temporal and/or biological relationship to test article administration. The event is unlikely to be related to an alternative etiology. There is a reasonable response on interruption/withdrawal of test article administrations (dechallenge). Rechallenge information is not required in this trial.
Definitely Related: The adverse event has a temporal relationship to test article administration and resolves when test article is discontinued. An alternative etiology is not apparent.
If a subject is discontinued from test article administrations for any reason, study site personnel must clearly report and document the circumstances and data leading to any discontinuation using the case report forms. It must be determined if the reason for stopping test article administration is an adverse event, for example, symptomatic bleeding associated with drug administration. Adverse events that required discontinuation of dosing or withdrawal of the subject from follow-up should be treated as a medical event of interest (MEOI) and detailed on the SAE form in the EDC system.

6. Outcome Resolved Ongoing Died
Document the outcome of the event as resolved, ongoing, or died. If the event is ongoing, follow the patient until the event resolves or until the event is confirmed as ongoing at the day 365 follow-up visit, whichever comes first. If the subject dies and the event was ongoing up until the time of death, then the outcome will be recorded as “died.”

7. Serious Adverse Event Resulting in death Life-threatening
Requiring or prolonging inpatient hospitalization
Disabling/Incapacitating
Opinion of the investigator/medical monitor
Serious adverse events (SAE) are adverse events which result in any of the following outcomes.
The adverse event caused or led to death. This is considered an SAE whether or not attributable to test article.
The adverse event placed the patient at immediate risk of death. A classification of life-threatening does not apply to an adverse event that hypothetically might have caused death if it were more severe.
The adverse event required at least a 24-hour inpatient hospitalization or prolonged a hospitalization beyond the expected length of stay. Hospitalizations for elective medical/surgical procedures, scheduled treatments, or routine check-ups are not serious adverse events by this criteria.
The adverse event resulted in a substantial disruption of the patient’s ability to carry out normal life functions.
If an event does not meet any of these criteria but in the opinion of the investigator or medical monitor may jeopardize the patient or may require medical or surgical intervention to prevent one or more of these outcomes, then the event should be reported as an SAE.

8. Additional Reporting Medical events of interest (MEOIs)
Compulsory SAEs
Medical events of interest (MEOIs) must be reported to the CC for Safety Event Committee review. Examples of MEOIs are Ventriculitis/Cerebritis/Meningitis, any cerebral bleeding event, hydrocephalus requiring a VP shunt, all AEs or SAEs related to a death within 30 days of randomization, AEs or SAEs requiring discontinuation of dosing or withdrawal from follow-up, suspected test article overdose whether or not clinically significant, any event resulting from a protocol violation. MEOIs will be listed in the AE dictionary. If a MEOI is chosen from the drop-down list on the Adverse Event form, the system will require you to complete a SAE Report form to provide information similar to a serious adverse event.
Compulsory SAEs are defined as any event coded as a grade 4 or 5 on the AE form in the EDC and will require reporting as serious adverse event using the SAE Report form in the EDC.

9. Reporting All AEs/SAEs through Day 7 Day 8 through Day 365
Neurological AEs
SAEs
Deaths
Reported directly into the Vision database
The forms used for data collection were discussed earlier.
ALL adverse events and serious adverse events will be reported using the EDC system through Day 7 post randomization.
All neurologic adverse events and any alarming, serious, or unexpected adverse event, including death due to any cause, which occurs during this study will be reported using the EDC beginning with Day 8 post randomization and ending with the D365 follow-up visit. These events will be reported whether or not they are thought to be related to the administration of test article and must be reported immediately (within 24 hours of learning of the event) to the Coordinating Center.
During follow-up visits in the clinic or on the telephone, you should try to elicit adverse events by asking simple questions. There are multiple examples of this but a few are: How have you felt since your last visit? Or Have you had any health problems since you were here last? Or Have you been hospitalized since the last follow-up visit? If yes the answer is yes, you should then ask if the hospitalization was for placement of a ventriculoperitoneal shunt?
You must complete an entry in the EDC system within 24 hours of discovery of any serious adverse event. The system will immediately notify the safety officer and the QA monitor by that an event has occurred.

10. Medical Monitors Who are they? What do they do?
Medical Safety Monitor: Carlos Kase, MD
ICU Complications Monitor: Juan Carhuapoma, MD
What do they do?
There are two medical monitors for this trial.
The Medical Safety Monitor is Dr. Carlos Kase from Boston University. Dr. Kase will review all SAEs and MEOIs that occur through day 365 to determine the relatedness of the event to test article and compliance with the protocol. Dr. Kase has access to the EDC system and will review all available data entry, source documentation, and imaging as needed for his review of the events.
The ICU Safety Monitor is Dr. Juan Carhuapoma from Johns Hopkins University. Dr. Carhuapoma will review all SAEs and MEOIs that occur through day 7 to determine the relatedness of the event to the test article and compliance with ICU care protocols.

11. Safety Event Committee
What is it?
Why should you care?
The Safety Event Committee is made up of the study chairman, the safety officer, one neurosurgeon, one neurointensivist, and one study coordinator. The committee reviews all neurologic adverse and serious adverse events identified by the site, monitor, safety officer, central reading center, or the surgical center. The committee is tasked to adjudicate the occurrence of the event, the classification of the event, the onset of the event, the relatedness of the event to test article, whether or not the event was symptomatic, and whether or not the protocol needs to be revised due to the occurrence of the event.
This is important to you because the committee may request that you to add an event, reclassify an event, move an event to medical history if the onset of the event is found to occur prior to randomization, or even, in rare instances, to delete an event.