Chapter 8: Safety, Adverse Events and Endpoints

Table of Contents Chapter 8: Safety, Adverse Events and Endpoints... 8-1 8.1 The ACLAIMS Safety Officer... 8-1 8.2 Adverse Events (AE)... 8-1 8.3 Serious Adverse Events (SAEs)... 8-2 8.4 Classifying Adverse Events... 8-2 8.4.1 Expectedness (Anticipated or Not Anticipated)... 8-2 8.4.2 Relatedness... 8-2 8.5 Reporting Adverse Events... 8-4 8.5.1 Adverse Event (non-serious) Reporting... 8-4 8.5.2 Serious Adverse Event Reporting... 8-4 8.5.3 Initial expedited reporting of SAEs in the database... 8-4 8.5.4 Steps for completing an initial SAE report... 8-5 8.5.5 Information Needed for SAE Reporting... 8-5 8.5.6 Narrative Guideline... 8-5 8.5.7 SAE Follow-up Information... 8-6 8.5.8 Other Reporting Requirements... 8-6 8.6 ACLAIMS Endpoints... 8-6 8.7 Clinical Site Procedures for Data Collection... 8-6 8.7.1 Data Collection Forms Related to Endpoints... 8-7 8.7.2 Event Narrative Form (ENF)... 8-7 8.8 Monitoring Potential Endpoints... 8-7 8.9 Additional Source Documentation... 8-8 Guideline for Completing the Event Narrative... 8-9 ACLAIMS Study Reference Manual Version 1.0 February 14, 2011

Chapter 8: Safety, Adverse Events, and Endpoints 8.1 The ACLAIMS Safety Officer Thomas Smith, MD, is available to discuss Serious Adverse Events (SAEs) and decisions about whether patients with SAEs or other clinically significant problems can continue taking study medications. Dr. Smith is also responsible for making sure SAE reports are complete and adequate to meet reporting requirements. If any of the events below occur AND the patient and study physician want to continue study medication, the Safety Officer must be consulted: Any hospitalization Worsening tardive dyskinesia. Weight gain of 15 pounds or more (from baseline). Increase in LDL cholesterol of 20 mg/dl (from baseline). New onset diabetes mellitus. Significant clinical worsening as indicated by increased CGI score. The Safety Officer will need to approve the continuation of study medication and a plan for follow-up. All communications with the Safety Officer should come from the study physician. Thomas (Tom) Smith, MD Tel: 212 543-5976. Messages left after 5 pm ET may not be answered until the next business day. Immediate attention: Mobile: 917 763-8727 Email: tes2001@columbia.edu 8.2 Adverse Events (AE) An Adverse Event (AE) is defined as any untoward medical occurrence in subject which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding for example), symptom, or disease temporally associated with the use of a drug, whether or not considered related to the drug. For this study, clinically significant abnormal laboratory findings must be reported as AEs (Adverse Events). Abnormal findings or occurrences judged not clinically significant need not be considered adverse events. Any condition that existed at the time of study enrollment is not an AE unless there is a change in the nature, severity or degree of the condition. Pre-existing conditions should be recorded at baseline on the Medical History form. 8.3 Serious Adverse Events (SAEs) A Serious Adverse Event (SAE) is any untoward medical occurrence that: Results in death Is life-threatening ACLAIMS Study Reference Manual Version 1.0 February 14, 2011 8-1

Requires inpatient hospitalization or prolongation of existing hospitalization Results in persistent or significant disability/incapacity Is a congenital anomaly/birth defect Is medically significant (per Investigator s judgment) Overdose (per investigator s judgment) Life threatening, prolong, important medical event, and overdose, all offer some room for clinical judgment as to definition and as to whether a given event represents a reportable SAE. If in doubt, please consult with the project Safety Officer to help make this determination. Timeframe for Reporting SAEs Any SAEs that occurs from the time a patient enrolls by signing the informed consent form until 30 days after leaving the study must be reported. SAEs must be reported in the DMS within 24 hours of occurrence or 24 hours after site becomes aware of occurrence. 8.4 Classifying Adverse Events The definition of serious adverse events (above), not the severity of an event, determines what is specified as an SAE. For example, severe nausea is not considered an SAE unless it requires hospitalization or meets another SAE criterion. SAEs are classified according to expectedness and relatedness of an event to the study intervention. 8.4.1 Expectedness (Anticipated or Not Anticipated) Investigators must provide an assessment of whether SAEs are anticipated or not anticipated based on current knowledge found in the protocol, investigator brochure, product insert, or label. Categories are: Not anticipated (Unexpected) Any serious adverse event that is not protocol-defined or documented in the patient consent form or package insert. Expedited reporting is required for serious adverse events that are unexpected and are possibly or probably related to participation in the research. Anticipated (Expected)- An event that is known to be associated with the intervention or condition under study. 8.4.2 Relatedness Investigators must provide an assessment of whether the SAE is related to the study intervention and/or study participation: Related: Adverse events that, after careful medical evaluation, are considered with a high degree of certainty to be related to the experimental intervention. An SAE should not be considered related simply because the event occurred during the course of the study. There should be a specific reason that the event is considered related to the study drug. The following criteria will apply: ACLAIMS Study Reference Manual Version 1.0 February 14, 2011 8-2

Followed a reasonable temporal sequence from administration of trial intervention, And/or followed a known response pattern to the trial intervention, And could not have been produced by other factors such as the patient s clinical state, or other therapeutic intervention Probable: There is a reasonable probability, based on the above criteria, that the experience may have been caused by the drug. Possible: Adverse events that, after careful medical evaluation, do not meet the criteria for a probable relationship to the experimental intervention, but for which a connection cannot be ruled out with certainty. In general, an exacerbation of illness is considered possibly related to the study antipsychotic. The following characteristics will apply: o o The event occurs after experimental intervention, and The event is not a known reaction to experimental intervention, but cannot be explained by a commonly occurring alternative etiology Unlikely: The experience was most probably produced by factors other than the trial intervention such as the patient s underlying clinical state, or concomitant therapy, and does not follow a known response pattern to the experimental Intervention. The following characteristics will apply: o o The event does not follow a reasonable temporal sequence from administration to the experimental intervention, or May have been produced by environmental factors, and there is no apparent pattern of response to the experimental intervention Not related: The experience is clearly related to other factors such as the patient s clinical state, therapeutic intervention or concomitant therapy SAE Clarifications Death is always an SAE. If the adverse event is listed in the package insert, it is not unexpected. All new-onset seizures or malignancies should be considered SAEs. Life threatening, prolong, important medical event, and overdose, all offer some room for clinical judgment as to definition and as to whether a given event represents a reportable SAE. For example, if a patient forgets to take his medication on Monday and takes his medication for both Monday & Tuesday on Tuesday, this probably does not need to be reported. However, if a patient ingests a month s supply of study drug in a suicide attempt this certainly should be reported. Pregnancy requires an administrative discontinuation of study medication. Study assessments may continue. All pregnancies that occur while a woman is participating in the ACLAIMS should also be followed to completion and the outcome reported, only then can any risk of congenital anomaly or birth defect be determined (requiring and SAE report). If a patient becomes pregnant during the study, please contact the ACLAIMS Safety Officer immediately. ACLAIMS Study Reference Manual Version 1.0 February 14, 2011 8-3

8.5 Reporting Adverse Events Adverse Events (AEs), Serious Adverse Events (SAEs), and Unexpected (Unanticipated) Problems have specific reporting procedures and should be reported accordingly 8.5.1 Adverse Event (non-serious) Reporting Adverse events (non-serious) are reported on the Adverse Events / Side Effects Form (AES) based on the protocol specified schedule. The AES form consists of two sections; 1) a systematic inquiry addressing specific adverse events that have been commonly reported by patients taking the study drugs included in this trial, and 2) a general inquiry offering the patient to bring up other complaints. Record events that occurred since the last study visit on the AES form. The clinician s rating of the severity of event/effect is recorded for each event. The rating should be based on the clinician s judgment of greatest severity of the AE since the last study visit. 8.5.2 Serious Adverse Event Reporting All SAEs must be initially reported to the DCC within 24 hours after a site becomes aware of an occurrence. Please note that an SAE is not considered reported until entered into the DMS. In addition, the site should notify the DCC of an SAE in the system by calling the Help Line (1-866- 659-3064) and providing the Participant ID and Visit number (a voicemail message is acceptable). The initial report should be followed by a more detailed written SAE report as soon as possible. Follow up information may be required and asked for by the safety officer directly, or by an independent safety monitoring body. In addition the investigators are expected to comply with their institutional policies with regard to reporting to the FDA any serious, unexpected drug events for any drug used in patients participating in this protocol. As indicated in the FDA guidelines If the drug is marketed and not under an IND (21 CFR 314.80[(c) (1) (i)], a serious and unexpected adverse drug experience must be reported to the FDA within 15 calendar days of initial receipt of the information by the applicant This reporting should be submitted on a MedWatch Online Voluntary Reporting form (3500) at https://www.accessdata.fda.gov/scripts/medwatch/. A copy of this form should be faxed to the DCC within 10 working days of reporting to the FDA. Some site IRBs may require reporting of other adverse events or experiences that do not fit the description above. This additional reporting is the site s responsibility (as is all IRB reporting), and is not part of study data collection. 8.5.3 Initial expedited reporting of SAEs in the Database Once the DCC is notified of an SAE entered in the DMS, the DCC will notify the study Safety Officer. If the study physician wants to consult with the Safety Officer at the time of completing an initial report, he or she should call the Safety Officer directly: Thomas (Tom) Smith, MD Tel: 212 543-5976. Messages left after 5 pm ET may not be answered until the next business day. Immediate attention: Mobile: 917 763-8727 Email: tes2001@columbia.edu ACLAIMS Study Reference Manual Version 1.0 February 14, 2011 8-4

8.5.4 Steps for completing an initial SAE report 1. Complete the SAE form with as much information as possible, following the Instructions for Completing the Serious Adverse Event Report in the SAE QxQ provided in Appendix 4. The PI or study physician should sign all completed SAE forms. If necessary, the clinician may wish to consult with the ACLAIMS Safety Officer. 2. Assign the appropriate visit# and seq#. For the initial report, use SEQ number 101. For any later updates to the form for this SAE, use SEQ 102, 103 and so on. If an unrelated SAE occurs on a participant at the same visit number, that Seq # series then begins with 201 3. Key the form into the DMS. 4. Call the DCC HelpLine to notify them of an SAE. 5. The DCC will review the data and send out queries if needed. 6. The DCC will notify and report the SAE to the Safety Officer. 7. The Safety Officer may request additional information on the Event 8. Queried typos and/or other small edits are allowed on the initial report, however, any follow-up information that updates this event must be recorded on a new SAE form that is documented as follow-up with the next Seq # 8.5.5 Information Needed for SAE Reporting 1. The Following information about SAE should always be provided: Timing of SAE Diagnostic Procedure if any Nature and Intensity Causality Information according to the investigator Action taken for the SAE, like, stopping the drug, etc. Outcome of SAE 2. Other Adverse Events: Only AEs related to the SAE should be mentioned. 3. Laboratory findings and Vital signs: Only those that are related to the SAE should be taken into account. 4. Information to Avoid: Do not include identifying information such as patient's name or initials, naming any form of geographic location such as names of hospitals or facilities, names of clinicians or study coordinators or any other identifiers. 5. Make sure dates in narrative correspond with dates on SAE form. Discrepancies in dates will result in a query. 8.5.6 Narrative Guideline Critical to the SAE report is a good narrative or detailed description of the event. It should provide rich, focused clinical detail regarding the signs, symptoms and lab values supporting the initial diagnosis, and listing all medications the patient was taking when the SAE occurred. An initial judgment as to relatedness and unexpectedness must also be included. ACLAIMS Study Reference Manual Version 1.0 February 14, 2011 8-5

The SAE form, detailed instructions for completing the SAE form, and examples of completed forms are in Appendix 4 of the SRM. Narrative guidelines are located in the final section of this chapter. 8.5.7 SAE Follow-up Information All SAEs must be followed until resolved. The following information helps to complete the SAE report: Providing additional clinical details as these become available, using the appropriate sequence (SEQ) numbers for each follow-up entry. Describe treatments undertaken and the results of these. Adjust judgments as needed regarding diagnosis, relatedness and unexpectedness. For date entry of follow-up information, do not update the initial data record that was entered under the 101 sequence number. A new record with an incrementing SEQ # should be created, but only the new information needs to be entered. The DCC and/or the Safety Officer will contact the site or study physician to complete this additional detail if needed. 8.5.8 Other Reporting Requirements Sites are responsible for IRB reporting to their own IRB. The DCC will provide all reports as appropriate to the Study Safety Officer, and to Columbia University for reporting to the governing IRB, NIMH, and the DSMB. 8.6 ACLAIMS Endpoints The primary endpoint or outcome measure for this trial is efficacy failure, i.e. inadequate control of the psychopathology of schizophrenia or schizoaffective disorder. This section focuses on the data collection procedures that will be necessary to identify and assess if an efficacy failure has occurred. Site investigators are responsible for providing the data needed to determine if a clinical endpoint has occurred. A blinded Outcome Adjudication Committee will make the final determination. 8.7 Clinical Site Procedures for Data Collection Each clinical site contributes to the endpoint classification process through complete and prompt data collection and data entry. Critical to this data collection is the Event Narrative Form (ENF). An ENF must be completed in all of the following situations: Any serious adverse event Any use of non-study antipsychotic after the first 8 weeks Any new start of medications to treat psychiatric symptoms on the AMR data collection form. Study medication discontinuation Any crisis intervention or significant change in treatment intensity In addition to providing data and information on the study s data collection forms, sites may be asked to provide additional essential source documents needed in the endpoints review process if requested by the Data Coordinating Center or Outcome Adjudication Committee. ACLAIMS Study Reference Manual Version 1.0 February 14, 2011 8-6

8.7.1 Data Collection Forms Related to Endpoints The following data collection forms include data helpful in the eventual determination that a study endpoint has occurred: Event Narrative Form (ENF) Reason for Assigned Treatment Discontinuation Form (RTD) Service Utilization and Resources Form for Monthly Items (SRF) Adjunctive Medication Record (AMR) Serious Adverse Events Form (SAE) Adverse Event / Side Effects Form (AES) 8.7.2 Event Narrative Form (ENF) It is the ENF form that ultimately provides the important information that is reported to the Endpoints Adjudication Committee. All of the data forms listed above have questions whose answers may trigger the need for an Events Narrative form (ENF), either automatically or through a query from the DCC. The ENF should provide the full description of a patient event. This narrative is a critical piece of information necessary to make the proper adjudication of an endpoint in this study. The narrative section includes a Clinician s Check List that details the specific information needed to be included in each narrative. Clinician s Check List: symptoms past history of similar symptoms suicidal thoughts, behaviors aggressive thoughts, behaviors overdose of any drug current substance use/abuse functional impairment length of time in ER adherence to adjunctive medications person initiating admission Each unique event requires a complete description within the narrative. Some of the information needed for a complete narrative may be available from the clinical sites records and participant report. Some may need to be collected from a non-study clinic, ER, hospital, other outpatient treatment program, possibly even from family reporting. Examples are provided in the last section of this chapter. 8.8 Monitoring Potential Endpoints The DCC will monitor and track all potential study endpoints for eventual reporting to the Endpoints Adjudication Committee. This is done through a variety of ways. 1. The site reports on and enters an SAE form if appropriate 2. The site enters other related data (ie SURF) and the ENF form ACLAIMS Study Reference Manual Version 1.0 February 14, 2011 8-7

3. The DCC will monitor data responses in the DMS that might trigger the need for an ENF form. The DCC will query the site for this form. 4. Clinical site monitoring will review for potential endpoints in patient records. Any of the above can begin the process of identifying and tracking potential endpoints, and begin a quality control (QC) process of checking for complete data entry, and, provoke any query reporting/resolution necessary to capture all information needed for potential endpoint reporting. 8.9 Additional Source Documentation In addition to the ACLAIMS data collection forms, supporting source documentation may be requested from a clinical site. The Outcomes Adjudication Committee (OAC) relies mainly on DMS data in order to determine whether endpoint criteria were met for a particular event. However, the committee may request additional source documentation if needed. All source documentation requested and submitted to the DCC must include the participant ID number, contact occasion and sequence number corresponding to the associated ENF form entered into the DMS. Source documentation must be filed locally in the participant s study binder/file. A cover sheet should accompany all source documentation being sent to the DCC, identifying the Participant ID, Visit and Seq number, and an inventory of documents attached. Use a separate cover sheet for each unique ENF (based on visit number and sequence number). All source documentation sent to the DCC must have personal identifiers removed or masked. Participant name, social security number, physician and other individual names, medical record numbers, and other identifiers deemed confidential by local regulations must be masked or adequately blacked out prior to submission to the DCC. Masked and labeled supporting documentation and cover sheet can be faxed to ACLAIMS DCC at 919-962-3265, or mailed to: ACLAIMS DCC CSCC-UNC Biostatistics Dept. 137 E. Franklin Street, Suite 203, CB# 8030 Chapel Hill, NC 27514-4145 ACLAIMS Study Reference Manual Version 1.0 February 14, 2011 8-8

GUIDELINE FOR COMPLETING THE EVENT NARRATIVE NOTE: Although Serious Adverse Events will trigger an Event Narrative, SAE reports and Event Narratives have different purposes. SAE reports are needed to help IRBs and the DSMB understand the safety of the study treatments and procedures the relationship between the SAE and the study medication is critical. Event Narratives are necessary to help our independent and blinded Outcomes Adjudication Committee determine if an efficacy failure has occurred and thus require more information about symptoms and behaviors, and less about laboratory values and other medications, compared to SAE reports. Narrative Guideline 1. Following information about any event signifying a possible efficacy failure (EF) should always be provided: Timing of event Description of Event including symptoms and behaviors Circumstances surrounding event Action taken (e.g., used oral medication, stopped LAI, none needed) Outcome of event or relevant subsequent events 2. Information to Avoid: Do not include identifying information such as patient's name or initials, naming any form of geographic location such as names of hospitals or facilities, names of clinicians or study coordinators or any other identifiers. 3. Make sure dates in narrative correspond with dates on other forms. Discrepancies in dates will result in a query. 4. Other Adverse Events: Only AEs related to the event should be mentioned. Guideline for Writing Descriptive Narrative The Event Narrative should be written in the order that follows. Please give special attention to the order of the information you provide. The narrative should be typed in Word and when proofed and final, copied and pasted into the DMS. Copy and paste the contents of the document into a DMS note log on Item 14 on the SAE form or Item 4 on the ENF form respectively. Specific details for each form are found in the Study Reference Manual, Appendix D-Forms and QxQs a) Open the narrative document and select select all from the Edit menu on the WindowsTool Bar. Then select copy from the same menu b) Minimize the document and then open the ENF or SAE form in the DMS. c) With the curser on the data field (Item 14 SAE, Item 4 ENF), select note log from the problems menu d) Use the key combination SHIFT + INSERT to paste the document into the note log. e) Save the note log by using the key commands (ALT + S) ACLAIMS Study Reference Manual Version 1.0 February 14, 2011 8-9

FIRST PARAGRAPH 1) Subject ID (this is necessary to verify that the correct narrative is associated with the proper record) 2) This year-old man/woman was randomized to study treatment on XX/XX/XX. 3) A description of the event (e.g. hospitalization, addition of another antipsychotic, discontinuation of study antipsychotic, increased intensity of service provision) and what led to it. Provide dates of key occurrences, including the dates of suicidal behaviors, hospitalizations, medications started, etc. Explain rationale for clinical interventions, and their effects. 4) List and provide description of symptoms or behaviors that are related to the event and their outcome. 5) Medical or psychiatric conditions relevant to the event. NEW PARAGRAPH: 6) Outcome of the event. Was the study drug continued? Did the patient continue to participate in the study? OPTIONAL NEW PARAGRAPH: 7) Other related events can be mentioned. The relationship of these events and their outcomes should be provided. The following Event Narratives are examples that follow the order of the sentences above to form the complete body of the narrative. Narrative Example #1 Subject D014000: This 21-year-old woman was randomized to study treatment on July 25, 2010. On December 10, 2010 she was admitted to the hospital with increased paranoid ideation and auditory hallucinations. She had been doing well at the time of her last injection in November and had not missed any recent injections. In recent days her parents report that she had been increasingly agitated and ultimately yelled at family members in response to auditory hallucinations and threatened to hit her mother. She was taken to an emergency room by her sister and admitted to an inpatient psychiatric unit. There she was started on PO olanzapine 20mg. She was discharged from the hospital on December 17, 2010 on olanzapine with symptoms much improved. The patient informed us by telephone that she no longer wanted to take study medication so it was discontinued. She did not want to continue participation in the study in any way. We did not see her again. Narrative Example #2 ACLAIMS Study Reference Manual Version 1.0 February 14, 2011 8-10

Subject D014001: This 41-year-old woman was randomized to study treatment on January 1, 2010. On July 10, 2010 she was admitted to the hospital after she broke her leg in a car crash in which she was a passenger. Her chronic mild auditory hallucinations at the time of the hospitalization were unchanged from baseline. She was discharged from the hospital after two days following an orthopedic procedure. During the hospitalization she received oral quetiapine at bedtime from the on-call psychiatrist (who did not try to reach the study doctors). The study physician discontinued the quetiapine when the patient received her next scheduled injection. She took quetiapine for 17 days. She did well over the next month and continued study treatment. Narrative Example #3 Subject D014002: This 21-year-old woman was randomized to study treatment on July 1, 2010. On September 21, 2010 she called the study team to report increased auditory hallucinations. Her symptoms were at baseline and under good control at the time of her last injection at the end of August. She was seen in the clinic on September 21 by the study psychiatrist and found to be appropriate for continued outpatient care, with good self-care, no appreciable suicidal or homicidal risk, and no other prominent symptoms besides the increased auditory hallucinations. Oral risperidone 2mg was added at bedtime, and the hallucinations diminished significantly up until the time of her next study visit. The dose of her LAI was increased on October 6, 2010 when she received her next scheduled injection. The study doctor recommended that she continue with risperidone for another week but she reported sedation and did not want to continue the oral medication. She took oral risperidone for 15 days. Symptoms remained absent for the next month. Narrative Example #4 Subject D014002: This 28-year-old woman was randomized to study treatment on March 1, 2010. On October 15, 2010 when she came in for her scheduled injection she reported that she no longer wanted to take an injectable medication. Her chronic auditory hallucinations remained present at a low level, but much improved since her last hospitalization in February. There was no change in her clinical status since the last visit. She denied suicidal and homicidal ideation, denied any delusions, was neatly dressed and appropriate. She was willing to continue with an oral antipsychotic medication but no longer wanted to participate in the study in any way and said she would like to follow up with her previous outpatient psychiatrist. Oral risperidone was begun and the study team made a follow up appointment for the patient with the previous psychiatrist. We did not see her again after October 15, 2010. Narrative Example #5 ACLAIMS Study Reference Manual Version 1.0 February 14, 2011 8-11

Subject D014002: This 29-year-old man was randomized to study treatment on May 1, 2010. On September 22, 2010 when he came in for his scheduled injection he reported that the entity that had long controlled his actions was becoming increasingly malevolent and refusing to allow him to drink water during daylight hours. In addition voices were becoming more frequent and commenting on his eating and drinking habits. Sleep was decreased but still 5 hours per night. There was no suicidal or homicidal ideation. Patient appeared distressed but well dressed and nourished. The dosages of LAI were increased to the maximum allowed by the study. The study physician also added quetiapine 100 mg at bedtime. At follow-up one week later sleep was improved but delusions and hallucinations unchanged. Quetiapine was increased to 200 mg qhs. Patient reported feeling better one week later, with improved sleep, no AH, and less preoccupation with delusions. He was eating and drinking normally. The patient and doctor agreed to continue quetiapine 200 mg qhs along with the maximum dose of LAI. One month later, on November 20, 2010 he was doing well. The quetiapine was tapered over the next two weeks but hallucinations returned. Quetiapine was increased to 200 mg and symptoms improved. Study medication was discontinued because it was determined that LAI monotherapy was not sufficient. The patient continued on quetiapine 200 mg. He still participates in follow-up assessments. ACLAIMS Study Reference Manual Version 1.0 February 14, 2011 8-12