MOST Clinical Performing Site Study Drug Procedures

Transcription

1 Abbreviations and Definitions MOST Clinical Performing Site Study Drug Procedures ACS AIS Arm Acute Coronary Syndrome Acute Ischemic Stroke Argatroban (100µg/kg bolus and a 12-hour infusion at 3µg/kg/min) Eptifibatide (135µg/kg bolus and a 2-hour infusion at 0.75µg/kg/min) Placebo Auromedics CCC CPS CRF Eagle GMP HIT IND Lot LTC MUSC NCC NCC Central Pharmacy NDMC NIH Supplier of commercially available Eptifibatide Clinical Coordinating Center Clinical Performing Site Case Report Form Supplier of commercially available Argatroban Good Manufacturing Practice Heparin-Induced Thrombocytopenia Investigational New Drug A batch of study drug to be packed Lead Trial Coordinator Medical University of South Carolina NIH StrokeNet National Coordinating Center StrokeNet NCC Central Pharmacy located at the University of Cincinnati- study drug distribution center StrokeNet National Data Management Center at the Medical University of South Carolina (MUSC) National Institutes of Health Study Drug Kits Subjects will receive a study drug kit with three vials of one of the following: 1. Argatroban (1mg/ml) bolus in 100 ml vial + Argatroban (1 mg/ml) 2-hour infusion in 100 ml vial + Argatroban (1mg/ml) 10-hour infusion in 250 ml vial 2. Eptifibatide (1.35 mg/ml) bolus in 100 ml vial + Eptifibatide (0.25 mg/ml) 2-hour infusion in 100 ml vial + placebo 10-hour infusion in 250 ml via Draft v0.8_19dec2018 MOST Stroke Trial Page 1 of 22

2 3. Placebo bolus in 100 ml vial + Placebo 2-hour infusion in 100 ml vial + placebo 10-hour infusion in 250 ml vial Study Drug Vials UC Davis WebDCU TM Argatroban (1mg/ml) 10ml bolus in 100 ml vial Argatroban (1mg/ml) 40ml infusion in 100 ml vial Argatroban (1mg/ml) 240ml in 250 ml vial Eptifibatide (1.35 mg/ml) 10ml bolus in 100 ml vial Eptifibatide (0.25 mg/ml) 40ml infusion in 100 ml vial Placebo 10ml bolus in 100 ml vial Placebo 40ml infusion in 100 ml vial Placebo 240ml in 250 ml vial University of California, Davis GMP study drug manufacturing Web based Clinical Trial Management System (CTMS) containing a web-based study drug shipping and management component, which allows for automated maintenance of the appropriate amount of study drug at the enrolling clinical performing sites and pharmacy depots Draft v0.8_19dec2018 MOST Stroke Trial Page 2 of 22

3 Contact Information StrokeNet NCC Central Pharmacy Study drug shipments, handling and maintenance Susan Seddoh PharmD Lindsay Vandergriff, CPhT II University of Cincinnati Holmes Hospital Room Albert Sabin Way ML 0405 Cincinnati, OH Phone: Fax: MOST CCC Lead Trial Coordinator Temperature excursions and protocol-related questions S. Iris Deeds, CCRP Lead Trial Coordinator University of Cincinnati Department of Emergency Medicine 231 Albert Sabin Way MSB Mail Loc-0769 Cincinnati, OH Phone: NDMC at MUSC WebDCU interfacing and troubleshooting Holly Pierce, MS Data Coordination Unit Medical University of South Carolina 135 Cannon Street, Suite 303 Charleston, South Carolina Phone: WebDCU interfacing and troubleshooting Jocelyn Anderson, MPH Data Coordination Unit Medical University of South Carolina 135 Cannon Street, Suite 303 Charleston, South Carolina Phone: StrokeNet NCC MOST Project Manager Regulatory and study logistics Dana R. Acklin Winfrey, BA Clinical Research Project Manager NIH StrokeNet National Coordinating Center University of Cincinnati Academic Health Center Department of Neurology 260 Stetson Street, Suite 5221B ML 0525 Cincinnati, Ohio Telephone: (513) Draft v0.8_19dec2018 MOST Stroke Trial Page 3 of 22

4 Introduction and General Study Drug Information Argatroban, a direct thrombin inhibitor, is FDA approved for use in patients who have or are at risk of developing heparin-induced thrombocytopenia (HIT). Eptifibatide, a glycoprotein IIb/IIIa inhibitor, is FDA approved for use in patients with Acute Coronary Syndrome (ACS) and in patients undergoing Percutaneous Coronary Intervention (PCI). The MOST trial is investigating the safety and efficacy of treatment with argatroban and eptifibatide compared with placebo in acute ischemic stroke (AIS) patients treated with 0.9mg/kg IV rt-pa within three hours of symptom onset. This trial is operating under an Investigational New Drug (IND) application. Both active medications are commercially available and will be manufactured at the required formulations for the study by the University of California (UC) Davis, an accredited Good Manufacturing Practice (GMP) facility. The study drug will be supplied in 100 ml and 250 ml glass vials as an intravenous solution. Study drug stoppers will allow for aspiration of study drug into a syringe for bolus administration, and for both line and syringe infusion pump administration. Administration of study drug should be via a dedicated IV line. Study drug will be administered per a weight based dosing protocol with a maximum weight of 100kg. Drug Manufacture, Supply and Distribution Eagle is the supplier of Argatroban 1mg/ml. Auromedics is the supplier of Eptifibatide 2mg/ml. Both medications will be procured by the MOST Trial team and shipped to UC Davis for repackaging (argatroban) and reconstitution and repackaging (eptifibatide). The study drug vials will be prepared by UC Davis and shipped to the NCC Central Pharmacy who will distribute study drug kits to participating Clinical Performing Sites (CPSs). Formulation, Packaging and Labeling Formulation Each drug and its matching placebo are liquid and identical in appearance. No reconstitution of study drug and placebo are required. Drugs provided will include: Vial #1: Argatroban bolus: (1 mg/ml)10 ml in 100 ml vial Vial #2: Argatroban 0-2 hour infusion: (1 mg/ml) 40 ml in 100ml vial Vial #3: Argatroban 2-12 hour infusion: (1mg/ml) 240 ml in 250ml vial Vial #1: Eptifibatide bolus: (1.35 mg/ml)10 ml in 100ml vial Vial #2: Eptifibatide 0-2 hour infusion: (0.25 mg/ml)40 ml in 100ml vial Vial #3: Placebo 2-12 hour infusion: 240 ml in 250 ml vial Vial #1: Placebo bolus: 10 ml in 100 ml vial Vial #2: Placebo 0-2 hour infusion: 40 ml in 100 ml vial Vial #3: Placebo 2-12 hour infusion: 240 ml in 250 ml vial Insert Vial Picture Here Draft v0.8_19dec2018 MOST Stroke Trial Page 4 of 22

5 Packaging Study drug for all study arms will be packaged into vials of 100 ml for the bolus and the 2-hour infusion dosing, and into a vial of 250 ml for the 10-hour infusion. All three vials will contain pre-mixed solutions of the study drug. Each vial of study drug will arrive sealed for the subject s protection. The vials will arrive to CPSs in kits. Kits will arrive tamper evident sealed and should NOT be opened before dispensing. Kits will be 7 x 7 x 3 inches in size and include three vials of the following sizes: ml vials ml vial Draft v0.8_19dec2018 MOST Stroke Trial Page 5 of 22

6 Labeling The study drug vials will be labeled with the following information: Vial 1 labels will include the following: Vial #1 (Bolus) MOST Trial, IND: Argatroban (1mg/ml), Eptifibatide (1.35 mg/ml) or Placebo I.V. Solution WEIGHT-BASED DOSING This vial contains 10 ml. Use as directed per study protocol. Administer ml over 3 minutes. Vial ID ##### 2-D Barcode corresponding to Vial ID Subject ID Caution: Limited by Federal (USA) Law to Investigational Use Only Lot number: # Storage temperature: 2-8 Celsius ( Fahrenheit) Manufactured by University of California, Davis Vial 2 labels will include the following: Vial #2 (0-2 hour infusion) MOST Trial, IND: Argatroban (1mg/ml), Eptifibatide (0.25 mg/ml) or Placebo I.V. Solution WEIGHT-BASED DOSING This vial contains 40 ml. Use as directed per study protocol. Administer ml/hr over 2 hours. Vial ID ##### 2-D Barcode corresponding to Vial ID Subject ID Caution: Limited by Federal (USA) Law to Investigational Use Only Lot number: # Storage temperature: 2-8 Celsius ( Fahrenheit) Manufactured by University of California, Davis Vial 3 labels will include the following: Vial #3 (2-12 hour infusion) MOST Trial, IND: Argatroban (1mg/ml) or Placebo I.V. Solution WEIGHT-BASED DOSING This vial contains 240 ml. Use as directed per study protocol. At start, administer ml/hr. Titrate per protocol. Vial ID ##### 2-D Barcode corresponding to Vial ID Subject ID Caution: Limited by Federal (USA) Law to Investigational Use Only Lot number: # Storage temperature: 2-8 Celsius ( Fahrenheit) Manufactured by University of California, Davis Draft v0.8_19dec2018 MOST Stroke Trial Page 6 of 22

7 The kit labels will include the following information: MOST Trial, IND: Kit ID ##### Subject ID 2-D Barcode corresponding to Kit ID Verification Code ### Argatroban, Eptifibatide or Placebo I.V. Solution This kit contains 3 study drug vials. Vial 1 contains 10 ml of Argatroban, Eptifibatide or placebo bolus Vial 2 contains 40 ml of Argatroban, Eptifibatide or placebo 0-2 hour infusion Vial 3 contains 240 ml of Argatroban or placebo 2-12 hour infusion Store at 2-8 C ( F) Use as directed per study protocol. Caution: New Drug Limited by Federal Law to Investigational Use Lot number: # Repackaged by StrokeNet NCC Central Pharmacy University of Cincinnati Holmes Hospital Room Albert Sabin Way ML 0405 Cincinnati, OH Do not open kit until dispensed. Expiration Date is available in WebDCU TM and may be extended as new information becomes available. Insert Kit Label Example Here Shipping, Receipt and Storage Shipping Study drug shipment requests will be automated by WebDCU TM and will be triggered when sites are released to enroll, subjects are randomized, or study drug is damaged/expired. CPSs must upload an institutional pharmacy license into WebDCU before study drug kits can be shipped to enrolling CPSs. CPS pharmacy shipping address must match the institution s pharmacy address listed on the license uploaded into WebDCU. NCC Central Pharmacy will receive the automated notification from WebDCU TM as study drug requests are posted. NCC Central Pharmacy will refer to WebDCU TM regarding the number of kits of each study drug type to be shipped to the CPS. No shipments will take place for receipt on Saturday, Sunday or holidays, unless absolutely necessary. When a CPS is released to receive study drug, study drug shipment requests will be automatically posted in WebDCU for 3 kits. When the CPS inventory reaches 2 kits, a study drug shipment request will be automatically posted in WebDCU for 2 more kits. Generally, a maximum of 4 kits will be kept at each CPS. A packing slip will be included with each shipment and will be available from WebDCU TM. An that will include a tracking number will be sent from UPS in order for the CPS to track a shipment. CPSs can track the package on the UPS website Study drug will be shipped with a USB temperature logger, cold packs, and enough insulation to maintain a temperature range of 2-8 C ( F) for at least 24 hours. Draft v0.8_19dec2018 MOST Stroke Trial Page 7 of 22

8 Receipt The CPS will receive an automated notification from WebDCU TM when study drug is shipped from the NCC Central Pharmacy. Sites will also receive an automated from UPS with a tracking number when the package containing study drug has been shipped and updates throughout the duration of transit. Upon receipt of the drug shipment, the CPS will verify the received study drug kits against the packing slip. If no discrepancies are identified, the CPS will confirm receipt of all study drug kits in WebDCU TM. If study drug kits are not marked as received in WebDCU within 2 days of shipment, the CPS will receive an automatic notification prompting them to receive study drug kits in WebDCU. Upon arrival of the shipment, the CPS will review the temperature data from the logger and confirm that the study drug did not experience any temperature excursions by documenting within WebDCU under the Drug Receiving tab and on the Study Drug Accountability Log. The CPS will print and store the temperature data printout in the CPS s MOST trial binder where the information will be reviewed during a monitoring visit. Once the data has been retrieved from the logger and the temperature curve is printed, the temperature logger can be disposed of per the institution s policy. See the next page for instructions on how to view and retrieve the temperature curve from the USB temperature data logger. A temperature excursion should be reported if shipment and/or storage temperature falls below 2 C (35.6 F) and/or rises above 8 C (46.4 F). If a temperature excursion has been experienced upon arrival of a shipment or during daily assessment of the storage area, the study drug should be quarantined and immediately marked as damaged in WebDCU. The CPS should report the temperature excursion using the Study Drug Temperature Excursion Form (Appendix B) and must notify the MOST LTC, Iris Deeds ( ), for further review. If a temperature excursion is marked in WebDCU, the MOST LTC and the CPS will receive an automatic notification prompting the CPS to contact the MOST LTC and to complete the Study Drug Temperature Excursion Form (Appendix B). The MOST LTC will follow-up with sites if no phone call is received within 24 hours. Only after CPSs verify that study drug did not experience any temperature excursions in WebDCU TM and confirm study drug kits as received in WebDCU TM will the study drug kits be available for randomization or resupply. Study drug kits should remain sealed until they are dispensed for a subject. Sites may refer to WebDCU training website ( for any issues with receiving study drug kits or reporting temperature excursions. Draft v0.8_19dec2018 MOST Stroke Trial Page 8 of 22

9 How to View and Retrieve the Temperature Curve from the USB Temperature Data Logger The USB temperature data logger will be activated by the NCC Central Pharmacy at the time the shipment is ready to be shipped from the NCC Central Pharmacy. The green flashing LED indicates that the data logger is recording data. *Note: DO NOT TEAR OPEN POUCH before data download* 1. Once the data logger arrives at the CPS, the CPS will STOP LOGGING by pressing the START/STOP button for 5 seconds. The red LED will flash 5 times, indicating that the data logger has stopped recording data. 2. To retrieve and view the PDF temperature curve report, tear open the protective plastic sleeve at the perforation to expose the USB. 3. Insert the data logger into a USB port of a computer at the CPS to view the PDF temperature curve report. 4. Optional-SET MARK: Press the START/STOP button 2 times in rapid succession to place a mark in the data report. Use SET MARK to mark a specific event, such as, arrival, or departure, or to acknowledge some other factor needing digital reporting. When logger is full or reaches fullcapacity of Marks, both Red and Green LED will flash simultaneously 3 times. If the datalogger shows a red flashing LED prior to the CPS stopping the data logger, an alarm has been triggered which may indicate a potential temperature excursion during shipment. Draft v0.8_19dec2018 MOST Stroke Trial Page 9 of 22

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11 Storage Study drug should be stored in a secure, limited-access to authorized personnel only location. Study drug should be stored at 2-8 C ( F). Study drug should be protected from excessive exposure to light. NDMC will update the expiration dates of study drug vials in WebDCU according to accelerated and ongoing long-term stability testing. WebDCU will generate an notification that will be sent out to the CPSs informing them of the drug extension date. The CPSs will be responsible for updating drug extension dates of study drug inventory per the CPSs institutional policies. Temperature Monitoring The CPS will maintain refrigeration between 2-8 C ( F) of study drug vials at all times. Storage areas where study drug will be kept must have a temperature monitoring system in place where study drug will be monitored continuously for temperature excursions. A sample Study Drug Temperature Log is provided for CPSs to use (Appendix A). CPSs may use their own institution-specific or electronic study drug temperature monitoring log to document temperature readings if such temperature log is deemed equivalent. The original Study Drug Temperature Log should be filed in the master file at the CPS and available for monitoring visits. Enrolling CPSs will be instructed to notify the MOST LTC, Iris Deeds ( ), of any temperature excursions that may have occurred during shipment, or if a temperature excursion is noted to have occurred during daily assessment of storage area. A temperature excursion should be reported if storage temperature falls below 2 C (35.6 F) and/or rises above 8 C (46.4 F). Should a temperature excursion occur, CPSs should immediately quarantine the study drug and mark it as damaged in WebDCU. The Study Drug Temperature Excursion Form (Appendix B) should be completed and submitted per instructions on the form. Randomization A web-based central randomization system will be developed by the NDMC and implemented through the WebDCU MOST study website. Once a subject has been deemed eligible and informed consent has been obtained, they may be randomized. To randomize a subject, the qualified MOST study team member will log in to WebDCU and complete the Subject Enrollment Form and Form 102 Randomization. WebDCU evaluates the treatment arm distribution and generates a Study Drug Kit ID based on the randomization scheme and corresponding to one of the study drug kits in inventory at the site. WebDCU will also generate weight-based dosing information. Upon completion of these forms, a qualified MOST study team member should immediately call their respective CPS pharmacy to alert them of need for study drug. Study personnel must print the Randomization Verification Form from WebDCU for source documentation. Please see Study Drug Dispensing Guidelines (Appendix C) for step-by-step instructions for Randomization and Dispensing. Draft v0.8_19dec2018 MOST Stroke Trial Page 11 of 22

12 Preparation, Dispensing, Administration, Documentation of Administration and Infusion Interruptions Preparation A qualified MOST study team member will print the Randomization Verification Form from WebDCU in order to retrieve the appropriate study drug kit ID. Once the study team member verifies the assigned study drug kit is dispensed by the pharmacy team, the study team member will sign the Randomization Verification Form. If it is the institution s standard pharmacy policies and procedures, the CPS pharmacist may prepare the weightbased bolus by drawing up the volume of the bolus from Vial 1 in the appropriate syringe. The seals of Vial 2 and Vial 3 should remain intact in the study drug kit when dispensed from the CPS pharmacy. Dispensing The CPS pharmacist/designee may prepare an individualized subject-specific label according to their institution s standard policies and procedures for labeling subject medication. These labels should be affixed to the individual syringe, if applicable, and study vials, not the kit box, after the kit has been assigned to the subject by WebDCU TM. These labels should not cover the study label. The CPS pharmacist/designee should verify the study drug vials are sealed by ensuring the vial seal is intact. If the seal is broken or tampered with, the study drug vial should not be dispensed for the study subject and it should be marked as damaged in WebDCU TM. The CPS should immediately report the finding to the individual on-call through the WebDCU Emergency Randomization Hotline ( ) for instructions on obtaining a new randomization number. The affected study drug should be destroyed at the CPS per institutional policy, or returned to the NCC Central Pharmacy for destruction if returning study drug is required per institutional policy. The CPS pharmacist/designee will document on the Study Drug Dispensing Log (see Appendix E) information about the study drug vials that are dispensed including the subject they are dispensed to. Study drug vials that are destroyed will be documented on the Study Drug Accountability Log (Appendix D). Administration It is likely that the study drug will be administered while rt-pa is still infusing, therefore a separate IV line that is dedicated to the 12-hour study drug regimen should be established. If a site is having trouble establishing separate IV access, call the MOST Clinical Hotline for guidance. Based on the institution s standard pharmacy policies and procedures, the weight-based bolus may be withdrawn from Vial 1 with the appropriate syringe by a CPS pharmacist, a qualified MOST study team member or a nurse or clinician at the subject s bedside. The weight-based bolus dose will be determined by WebDCU TM and should be administered within 60 minutes, but no later than 75 minutes from initial rt-pa bolus administration over a 3- minute IV push. Vial 2 will be dispensed from the CPS pharmacy sealed and should remain sealed until the bolus (vial 1) has been administered. After the bolus dose has been administered, the 0-2 hour infusion should be started immediately. The 0-2 hour infusion (vial 2) will be spiked and hung directly on an IV pole for administration through a pump. The infusion rate for vial 2 at 0-2 hours will be determined by WebDCU TM. Administration of the full dose prescribed for each participant will take 2 hours. Vial 3 will be dispensed from the CPS pharmacy sealed and should remained sealed until the contents of vial 2 have been administered. Within 2 hours after initial study drug bolus (+ 30 minutes), an aptt lab will be Draft v0.8_19dec2018 MOST Stroke Trial Page 12 of 22

13 collected via venous draw per local laboratory procedures. Finger stick aptt collection is prohibited. The aptt should be collected as early in the 2-hour (+ 30 minutes) window as possible to allow time for the sample to be processed and resulted. The baseline aptt will be entered into WebDCU by a qualified MOST study team member to populate the MOST Titration Table. The 2-12 hour infusion (vial 3) rate may be titrated based on the 2-hour aptt value according to the MOST Titration Table. Another aptt specimen collection will occur at 6 hours after initial study drug bolus (+ 30 minutes). Similarly, the aptt should be collected as early in the 6-hour (+ 30 minutes) window as possible to allow time for the sample to be processed and resulted. Again the 2-12 hour infusion (vial 3) rate may be titrated based on the 6- hour aptt value according to the MOST Titration Table. Collection of the aptt specimen should occur within the 2 hour (+ 30 minutes) window and similarly within the 6 hour (+ 30 minutes) window. If the timing of this activity falls outside the window, it should be recorded as a protocol deviation. Titration of the 2-12 hour infusion should occur as soon as possible after the 2 and 6-hour aptt. In the case that venous access has been lost after a participant is randomized into the trial, study infusions should be restarted as quickly as possible after the clinical team establishes access per standard practice. If a scheduled aptt draw is missed, the specimen should be collected, and the study drug titrated accordingly, as soon as possible. Documentation of Administration The total volume of the 2-12 hour study drug infusion (vial 3) administered to the participant may exceed or fall short of the volume of IP that was initially ordered due to the titration protocol. Therefore, it is imperative to maintain accurate documentation of the change in flow rates on the Study Drug Administration Case Report Form (CRF). It is advised that this CRF should be printed and available at the bedside, alongside the MOST Titration Table, for the duration of the infusion to capture the details every time a vial is changed, a rate is changed, or there is an interruption in the infusion. There is no need to keep the study drug vials after administration is complete as long as accurate accountability is ensured per the CPS institutional policy. Infusion Interruptions Interruptions to study drug infusion should be minimized as much as possible to ensure that the intended dose is administered to the subject. If an interruption to the 0-2 hour infusion (vial 2) occurs and is then restarted, the remainder of the dose in that vial should be completed. If the 0-2 hour infusion runs over the 2-hour time point, the aptt should still be collected at 2 hours (+ 30 minutes) after study drug bolus administration. The corresponding titration should not be performed until the 2-12 hour infusion (vial 3) is hung. If the 2-12 infusion is interrupted and then restarted, it should still be terminated promptly 12 hours after initial study drug bolus administration regardless of the duration of the interruption(s). If less than the intended dose and duration of study drug is administered to the subject, the reason why study drug was not administered in full should be documented on Form 206 Study Drug Administration. Draft v0.8_19dec2018 MOST Stroke Trial Page 13 of 22

14 Study Drug Timeline Graphic Draft v0.8_19dec2018 MOST Stroke Trial Page 14 of 22

15 Study Drug Accountability, Expiration/Damage and Destruction/Return Study Drug Accountability Each CPS is required to maintain study drug accountability records via the WebDCU TM system. Study drug receipt, dispensing, and damage/expiration/destruction should be documented in the system as described. Study Drug Accountability Logs will also be maintained by the CPSs recording study drug receipt, dispensing, and damage/expiration/destruction. See Appendix D for the Study Drug Accountability Log and Appendix E for the Subject Study Drug Dispensing Log. Current Study Drug Accountability Logs and WebDCU TM records should be available for review at the time of study monitoring visits. Additional internal recordkeeping documenting the details of the receipt and distribution of study medication may be required per local institutional policy. Study Drug Expiration/Damage WebDCU will send out automatic notifications to the sites within 30 days of expiration of the study drug. The site will mark any study drug kits that are expiring in WebDCU as expired. If an expiring study drug kit has not been marked as expired in WebDCU, another automatic notification will be sent to the sites within 14 days of expiration of the study drug. These kits may be destroyed according to the institution s standard policy and procedures, or may be returned to NCC Central Pharmacy if required by institutional policy for the destruction of sterile products as long as a record is maintained of what was destroyed. Study Drug Destruction/Return If expired/unused study drug is being returned, the Study Drug Return Form (Appendix F) must be completed and returned with the shipment. The study drug should be addressed and shipped to the NCC Central Pharmacy via the institution s preferred postal carrier. If study drug is being returned per institutional policy, shipping costs will be at the expense of the CPS. Package tracking information must be provided to NCC Central Pharmacy via . Returned study drug does not require temperature monitoring during transit, therefore a temperature logger does not need to be included with the shipment. Returned study drug to the NCC Central Pharmacy may not contain any subject identifiers. The CPS will report all dispensed/expired/damaged/replaced study drug kits in WebDCU TM and on the appropriate Study Drug Accountability Log prior to destruction of such vials taking place. Draft v0.8_19dec2018 MOST Stroke Trial Page 15 of 22

16 Appendix A SAMPLE Study Drug Temperature Log Draft v0.8_19dec2018 MOST Stroke Trial Page 16 of 22

17 Appendix B SAMPLE Study Drug Temperature Excursion Form Draft v0.8_19dec2018 MOST Stroke Trial Page 17 of 22

18 Appendix C SAMPLE Study Drug Dispensing Guidelines Study Drug Dispensing Guidelines 1 PATIENT ENROLLMENT AND RANDOMIZATION a) To randomize a subject, log into WebDCU and complete: 1. The Subject Enrollment Form 2. Form 102 Randomization CRF, and 3. Print the Randomization Verification Form ( link at top of the Randomization CRF), and supply to the pharmacy for dispensing) b) WebDCU evaluates the treatment arm distribution and generates a Study Drug Kit ID based on the randomization scheme that corresponds to one of the study drug kits in inventory at the site. WebDCU will also calculate the subject-specific doses per the weight-based dosing protocol. 2 STUDY DRUG AND aptt ORDERING An authorized prescriber will enter an order for each subject per institutional policy. The order may have the following: a) Subject enrolled in MOST Trial Protocol # b) Study Drug Kit ID c) Subject s name, date of birth and subject ID d) Vial 1: Argatroban, Eptifibatide or Placebo administered as IV bolus ( ml to be administered once intravenously over 3 minutes), followed by: e) Vial 2: Argatroban, Eptifibatide or Placebo 0-2 hour infusion ( ml/hr to be administered intravenously over 2 hours), followed by: f) Vial 3: Argatroban or Placebo 2-12-hour infusion (At start, administer ml/hr. Titrate per protocol.) g) Draw aptt at 2-hour ±30-minutes after initiation of study drug. Notify (insert investigator s name) of results for titration of study drug per protocol criteria. h) Draw aptt at 6-hour ±30-minutes after initiation of study drug. Notify (insert investigator s name) of results for titration of study drug per protocol criteria. i) NOTE: aptt labs may only be obtained intravenously, never by finger stick j) Authorized prescriber s signature and date signed 3 DRUG ASSIGNMENT AND DISPENSING a) Pick and verify the study drug kit corresponding to the study drug kit ID number on the Randomization Verification Form. Draft v0.8_19dec2018 MOST Stroke Trial Page 18 of 22

19 b) Print subject specific pharmacy labels per institutional policy, if applicable. c) If it is the institution s standard pharmacy policies and procedures, the CPS pharmacist may prepare the weight-based bolus by drawing up the volume of the bolus from Vial 1 in the appropriate syringe. d) Affix and flag the label onto the syringe (if applicable) and each of the study drug vials inside of the study drug kit. Do not cover the sponsor s original label. e) Ensure study drug vial caps are sealed and intact. f) Dispense study drug for administration. g) File Randomization Verification Form in subject record, h) Complete the Subject Study Drug Dispensing Log (any pharmacist or designee completing this log must verify their initials in this log). 4 SITE PHARMACIST OR DESIGNEE RESPONSIBILITIES a) Dispense study drug kit which will contain three vials. b) Maintain correspondence with sponsor and study personnel. c) Maintain accountability of used and unused study drug. d) Maintain USB Temperature Logger data for received study drug shipments in the MOST Pharmacy Binder for the duration of the study. e) Maintain Study Drug Temperature Log for storage temperature data on a daily basis and file in the MOST Pharmacy Binder for the duration of the study. f) WebDCU generates re-supply requests as subject enrollment occurs. g) Study drug vials should be destroyed on site, per institutional policy, after a subject has completed participation. Draft v0.8_19dec2018 MOST Stroke Trial Page 19 of 22

20 Appendix D SAMPLE Study Drug Accountability Log Draft v0.8_19dec2018 MOST Stroke Trial Page 20 of 22

21 Appendix E SAMPLE Subject Study Drug Dispensing Log Draft v0.8_19dec2018 MOST Stroke Trial Page 21 of 22

22 Appendix F SAMPLE Study Drug Return Form Draft v0.8_19dec2018 MOST Stroke Trial Page 22 of 22