Chapter 12.0: Test Article Preparation, Accountability, (Pharmacy Manual) and Administration

Transcription

1 Chapter 12.0: Test Article Preparation, Accountability, (Pharmacy Manual) and Administration Table of Contents: Randomization Treatment Drug Supply and Storage Drug Shipments General Information for All Sites North American (US, Canada, & Israel) Study Centers International Centers Drug Accountability and Documentation Admission Log Drug Accountability Log Subject Specific Log Personnel Responsible for Drug Preparation Preparation of Study Drug Preparation of Active Study Drug (Alteplase 2 mg vial) Deleted: Preparing Altiplase Syringe(s) to Freeze Deleted: Preparation of Active Study Drug Using Frozen Alteplase Syringe Preparation of Placebo Preparation of Flushes Labelling of Syringes Drug Destruction Catheter Irrigation (Test Article Administration Protocol) Sterile Technique/Preparation List of Abbreviations: C Celsius CC Coordinating Center cc Cubic Centimeter CSF Cerebrospinal Fluid CT Computed Tomography ecrf Electronic Case Report From EDC Electronic Data Capture EVD Extraventricular Drainage F Fahrenheit IVC Intraventricular Catheter IVH Intraventricular Hemorrhage JHH Johns Hopkins Hospital LAFW Laminar Airflow Workbench mg Milligrams ml Milliliters MRN Medical Record Number PI Principal Investigator rt-pa Recombinant Tissue Plasminogen Activator USP United States Pharmacopeia MOP 4 11 DEC 2013 Page 12-1

2 12.1. Randomization This is a double-blinded, multicenter, international, randomized study comparing the use of extraventricular drainage (EVD) combined with rt-pa to EVD combined with placebo (normal saline). The study is a two-arm, block-randomized design whereby blocks of eligible patients are randomized to treatment with EVD + rt-pa or EVD + placebo. Once a patient is determined to be potentially eligible for participation in the study, the site coordinator or a designated member of the study team at the site will enter the Inclusion/Exclusion information about the study subject into the VISION (Prelude Dynamics, Austin, Texas) web-based electronic case report form (ecrf) system. The system will process these subject variables, confirm eligibility and, if eligible, assign an identification number and treatment method to the patient. The randomization process is handled by an embedded software module; this module is part of the system and is invoked by the coordinator or investigator within the ecrf system. Randomization is triggered by the investigator or coordinator, via completion of a form in the ecrf, after all eligibility checks are performed. If the coordinator/investigator checks the randomize box and saves the form, the system will automatically set the enrollment date, assign a study ID and trigger the embedded randomization algorithm to determine the randomized treatment (including a final check to confirm the patient is still eligible). The implementation will be independently tested by the Biostatistics Center. The site coordinator is provided with a unique, blinded electronic treatment assignment number (randomized patient number) at the end of this process. Local study coordinators will provide site pharmacist contact information that will be entered into the system during site initiation. At randomization, the ecrf system will generate and send an or fax to the site pharmacist. This or fax will contain the blinded, treatment assignment along with information regarding when the 72-hour treatment window closes and the approximate, scheduled time for administration of first dose Treatment Active study drug, Alteplase 2 mg vials is provided for the study. 0.9% Sodium Chloride for Injection, USP will be used for the placebo. Enrolled subjects will receive either 1mg/ml of rt-pa, or 1ml of Normal Saline for Injection (placebo) every eight hours by intraventricular administration. The treatment will continue for up to twelve doses of either active or placebo study drug. Each administration will be performed via isovolumetric injection into the ventricle immediately followed by a flush of up to four (4) ml of 0.9% Sodium Chloride for Injection USP Drug Supply and Storage Study drug to be used for this trial is Alteplase two (2) mg vials for reconstitution. Alteplase is a recombinant tissue plasminogen activator (rt-pa) that is manufactured by Genentech, Inc. and Boehringer Ingelheim, Inc. Alteplase 2 mg Vials Each box and vial of Alteplase is labeled by the manufacturer, indicating the drug name, drug strength, quantify, log number, expiration date and storage recommendations. Alteplase vials are stored refrigerated at 2-8 C/36-46 F and protected from excessive light exposure. Do not use beyond the MOP 4 11 DEC 2013 Page 12-2

3 expiration date on the vial. Study drug must be stored in a secured area with limited access. The Alteplase study drug shall be dispensed in accordance with the authorized prescriber s written order to study subjects only. The Genentech product is supplied as Alteplase 2 mg (sterile powder for reconstitution) vials. After reconstitution the resulting solution must be used within 8 hours. One Alteplase 2 mg vial may be used to prepare two syringes if the next dose will be administered within 8 hours of reconstitution of the drug. Boehringer Ingelheim supplies five Alteplase 2 mg (sterile powder for reconstitution) vials and solvent per box. After reconstitution the resulting solution must be used within 24 hours. Use one Alteplase 2 mg vial to prepare two syringes. Discard the second syringe if the next dose will not be administered within 24 hours of reconstitution of the drug. All drug storage locations must have a system in place for daily monitoring of the temperature. For refrigerator storage an alarm and back-up power supply (i.e., generator) are also preferred. Variances in the storage condition of the study drug should be reported immediately to the coordinating center (CC) pharmacist. Supplies Sterile Water for Injection is the diluent used to reconstitute the Alteplase. Sterile Water for Injection is not included with the Genentech product but, it is included in the box with the Boehringer Ingelheim product. Other supplies used in the preparation of the study drug are not provided for the study. 0.9% Sodium Chloride Injection (preservative-free) for flush preparation should be taken from pharmacy supply, it will not be provided for the study Drug Shipments General Information for All Sites The site Principal Investigator (PI) is ultimately responsible for the handling of the study drug, which includes the receipt, accountability, and destruction of all drug supplies. The Pharmacy Department will manage the study drug including the receipt, preparation, accountability, and the proper destruction of the used vials at the time of study drug preparation North American (United States, Canada, and Israel) Study Centers The Johns Hopkins Hospital (JHH) Investigational Drug Service will send Alteplase study drug to each study site in Northa America and Israel. Each vial of study drug will have a manufacturer s label attached which will indicate the drug name, content per vial, storage information, lot number and expiration date. Each study drug box will have a Kit Number to be used for tracking purposes. Study drug will be shipped in multi-purpose insulated shippers with refrigerant packs to maintain the recommended storage temperature. Upon arrival, drug should be unpacked immediately, contents verified against the receipt record, and placed in a medication refrigerator. After reconciliation and MOP 4 11 DEC 2013 Page 12-3

4 completion of the requested information on the shipment receipt record, send a copy of the form by fax or to the JHH IDS (Investigational Drug Service) pharmacy as indicated on the form. Any inquiries regarding the integrity of the drug should be addressed with the coordinating center (CC) pharmacist. To reorder study medication communication will be sent to the CC pharmacist who will initiate shipment procedures International Centers (may include Israel) Purchase, storage and distribution of study drug to international centers will be undertaken by Mawdsleys Clinical Services or another in-country distributor. Mawdsleys or the distributor will purchase stock of Boehringer Ingelheim manufactured Alteplase. Study drug will then be distributed to international centers in accordance with instructions given by (JHMI) and/or Newcastle University Teaching Hospitals. All stock will be distributed in temperature validated containers including refrigerant packs with appropriate temperature monitoring. Each vial of study drug will have the manufacturer s label attached which will indicate the drug name, content per vial, storage information, lot number, and expiry date. Mawdsleys or the distributor will add a study specific label to each vial. Each box will also have a Kit Number to be used for tracking purposes. Upon receipt at the investigator site, the stock will be unpacked and transferred to a medication refrigerator and quarantined until approval for release of the supply is granted. The temperature monitoring device will be downloaded at the site and the data will be sent to Mawdsleys or the distributor for review. Any excursions will be identified and Mawdsleys or the distributor who will be report the excursion to the study CC pharmacist. All temperature excursions will be reviewed by the manufacturer or other qualified designee who will determine the outcome of the drug supply. To reorder study medication, communication will be sent to the study CC pharmacist who will provide the appropriate documentation to the distributor for shipping notification Drug Accountability and Documentation Each vial of Alteplase must be tracked by use of a study drug accountability form. Examples of a drug accountability form and other documentation forms are provided for your use at the end of this document. Electronic copies of the forms will also be provided. These forms may be altered to adhere with specific regulations at your institution or electronic documentation can be maintained. Please contact the study CC pharmacist for information regardin the forms or if major revisions to the forms are needed. Study related forms located in this section of the manual should be completed using black ink only. Corrections to documentation should be crossed out with a single line, initialed, and dated. The corrected information should be recorded next to the appropriate space. The following forms have been provided: MOP 4 11 DEC 2013 Page 12-4

5 Admission Log used to maintain a current list of all subjects enrolled in the study Drug Accountability Log used to document receipt of drug and disposition of the study drug a running balance must be maintained on each log Subject Specific Log used to document dispensing information for an individual subject Personnel Responsible for Drug Preparation All personnel responsible for the preparation of study drug must be trained to prepare sterile compounded preparations and receive training on protocol procedures. If your institution utilizes special procedures for intrathecal preparations, those procedures should be followed for preparation of study drug syringes Preparation of Study Drug Preparation of Active Study Drug (Alteplase 2mg vial) 1. Obtain Alteplase 2 mg study drug vial from the refrigerator 2. Utilizing aseptic technique in a laminar airflow workbench (LAFW) or barrier isolator (per USP 797 regulations; or using similar equipment consistent with local requirements), reconstitute the vial with 2.2 ml of Sterile Water for Injection (preservative-free). Do NOT use Bacteriostatic Water for Injection. For Boehringer Ingelheim manufactured Alteplase, use the ampule of sterile water provided with the study drug. 3. Slight foaming is not unusual; let the vial stand undisturbed for several minutes to allow dissipation of any large bubbles. Gentle rolling and tilting of the vial may be necessary to completely dissolve the powder. 4. DO NOT shake the vial; excessive or vigorous agitation may denature the drug. The reconstituted solution should be colorless to pale yellow and transparent. 5. Complete dissolution should occur within three minutes. 6. Resulting concentration after reconstitution is one (1) mg/ml. 7. Draw up 1 ml (1 mg/1m L) of the alteplase solution into a three (3) ml syringe. 8. Cap the syringe with a sterile rubber tip cap. 9. Label the syringe in a blinded fashion. 10. Place the final product into a plastic bag. Label the bag. 10. Obtain and complete a subject specific log. Record the time of reconstitution on the Subject Specific log (example attached). 11. Complete the drug accountability log (example attached). 12. The expiration date and time for the Alteplase syringe as follows: i. Genentech manufactured product is eight (8) hours after reconstitution when stored at 2-30 C (36-86 F). ii. Boehringer Ingelheim manufactured product is twenty-four (24) hours after reconstitution when stored at 2-8 C and eight (*) hours if stored at 25 C. MOP 4 11 DEC 2013 Page 12-5

6 13. More than one syringe can be prepared from the vial if the next dose will be administered within the recommended expiration time indicated above. 14. The used Alteplase vials can be discarded. (Based on product package insert for Cathflo Activase and Actilyse Cathflo) Preparation of Placebo 1. Obtain a vial of 0.9% Sodium Chloride for Injection 2. Utilizing aseptic technique in a laminar airflow workbench (LAFW) or barrier isolator (per USP 797 regulations; or using similar equipment consistent with local requirements), draw up 1 ml into a 3ml sterile syringe. 3. Cap the syringe with a sterile rubber tip cap. 4. Label the syringe in a blinded fashion. 5. Place the final product into a plastic bag. Label the bag. 6. The expiration date for the placebo syringe is as follows in order to match the active drug expiration date and time: i. Eight (8) hours when stored at 2-30 C (36-86 F) to match the active drug expiration date and time as prepared from Genentech manufactured product Twenty-four (24) hours after reconstitution when stored at 2-8 C and eight (*) hours if stored at 25 C to match the active drug expiration date and time as prepared from Boehringer Ingelheim manufactured product7. Complete the subject specific log 8. Complete the drug accountability log 12.8 Preparation of Flushes Each injection of study drug will be followed by up to 4 ml flush of 0.9% Sodium Chloride Injection (preservative-free). Send one 0.9% Sodium Chloride flush with each prepared dose of study drug. 1. Obtain 10 ml vial of 0.9% Sodium Chloride Injection, USP (Preservative Free). 2. Utilizing sterile technique in a laminar airflow workbench (LAFW) or barrier isolator (per USP 797 regulations; or using similar equipment consistent with local requirements), draw up 4 ml into a sterile 5 ml syringe. 3. Cap syringe with a sterile rubber tip cap. 4. Label the syringe. 5. Place the final product into a plastic bag. 6. Label the syringe bag. 7. Flushes expire in 24 hours. 8. Complete the drug accountability log. MOP 4 11 DEC 2013 Page 12-6

7 12.9 Labelling of Syringes Each syringe of Alteplase study drug must be labeled accurately. The study drug label shall contain the following: 1. Subject name or initials 2. Study name: 3. Study drug name: Alteplase 1mg/mL or Placebo 4. Volume of solution in the syringe: 1 ml 5. For Investigational Use Only 6. Expiration date/time of the drug The flush syringes should be labeled with the following: 1. Subject name % Sodium Chloride Flush (for study) 3. Volume of syringe: 4 ml 4. Expiration date/time The flush syringe should be labeled clearly so that it is not confused with the study drug syringe. Additional information may be added to the label to comply with your institutions policies and/or electronic system standards Drug Destruction All unused study drug may be discarded on site according to each site s specific policy for disposal of pharmaceutical waste. Prior to disposal of the drug, the CC pharmacist must receive a copy of the site s policy for study drug disposal (pharmaceutical waste disposal) and a completed drug destruction form to document the waste Catheter Irrigation (Test Article Administration Protocol) The prepared syringes containing the rt-pa or placebo and flush will be provided by the pharmacy to the appropriate study personnel for administration to the patient. The labels on the syringes must be compared with the patient s records to confirm identity. The first intraventricular injection will occur no sooner than twelve hours and no later than 72 hours after the initial bleed and only after confirming appropriate intraventricular catheter placement by head CT. After placement of any catheter a 6, or more, hour post surgical stabilization period is required prior to first or next injection of rt-pa. Viewing a video demonstration of the catheter injection protocol is mandatory before credentialing a center s physicians. After patient identity is confirmed, the drug will be administered as a sterile solution in preservative-free normal saline. A neurosurgeon or neurocritical care physician or their trained designee will perform intraventricular catheter injections under standard sterile technique using the process described below. MOP 4 11 DEC 2013 Page 12-7

8 Using a 3-way stopcock set-up is the ideal way to administer the drug. It allows for the catheter to drain while kept open to the transducer, measuring ICP during the injection and for the hour that the IVC is closed post injection, which is required by the protocol. The test article injection should be given as a push over a count of 20 seconds using the port closest to the head and with the least amount of drug space. Measure the length of tubing from the port of the head. The administration of the flush should follow and given as a push over a count of 20 seconds. The amount of flush administered is based on the amount of dead space in the tubing needed to be cleared. The flush should be isovolumetric with the corresponding amount of CSF withdrawn prior to test article (1ml) plus flush (up to 4 ml) injections. If you are unable to administer the flush due to high ICP, try and give at least part of the flush to account for dead space in the tubing while watching the ICP. Patient safety comes first. Document any departure from the flush administration protocol on the dosing form in the EDC system and in the medical record as source documentation Sterile Technique/Preparation a. Wash hands. b. Put on mask and sterile gloves. c. Close drainage system. d. Place sterile drape on field. e. Clean stopcock site with betadine/alcohol and allow to dry. MOP 4 11 DEC 2013 Page 12-8

9 f. Inject intraventricular catheter with syringe labeled study drug prepared by investigational pharmacy (normal saline placebo or rt-pa in a sterile solution) 1cc/minute g. Inject with syringe labeled flush to flush catheter. h. Maintain IVC closed for 60 minutes. i. Re-open IVC after 60 minutes at the level of the head until next scheduled dose. j. Repeat study drug administration every 8 hours for up to 12 doses or until dosing endpoint, whichever comes first. a. Criteria for dosing endpoints: i. IVH volume reduced to 20% of the initial clot volume as measured on the stability CT scan (surgical endpoint) ii. 3 rd and 4 th ventricles open with return of CSF flow iii. IVH related mass effect is treated iv. Complete 12 doses of study drug v. Clinically significant re-bleeding noted on daily CT scan vi. Subject withdraws consent vii. Family withdraws life-sustaining interventions A repeat CT scan will be performed within 24 hours of the stability CT and then repeated every 24 hours until the study is completed. No more than 3 doses should be given between daily CT scans. Repeat CT scans will be performed earlier than every 12 to 24 hours if or when the treating physician determines that there is a sustained worsening or improvement of neurological condition defined as a change in 2 points on the GCS motor scale score sustained for 8 hours. Therapy will be stopped at this time if there is resolution of IVH (third and fourth ventricles are open to CSF flow), any increase in hematoma volume, any intracerebral infection or emergence of systemic bleeding disorders. If residual hematoma volume on CT scan continues to equal or exceed 20% of the initial clot volume as measured on the stability CT scan or the third and fourth ventricles remain occluded, then instillation of the next dose of study drug will occur every 8 hours until hematoma volume falls below 20% and/or 12 treatments have been performed. MOP 4 11 DEC 2013 Page 12-9

10 ADMISSION LOG CLEAR PHASE III Principal Investigator: Site Number: DATE SUBJECT NAME SUBJECT NUMBER PHARMACIST INITIALS Original 4/09 JHH MOP 4 11 DEC 2013 Page 12-10

11 Subject Specific Sheet CLEAR PHASE III Subject Name: Investigator s Name: Subject # Site #: SUBJECT RANDOMIZED TO: Dose: Alteplase 1 mg (1mg/1mL) every 8 hours (total 12 doses) Date Dose # Time of reconstitutions Pharmacist s Initials Comments Original 4/09; rev Dec 2013 MOP 4 11 DEC 2013 Page 12-11

12 Drug Accountability Record PAGE OF Principal Investigator: IRB# Site: Title of Study: Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III Drug Name, Strength, & Dosage Form: Alteplase 2mg/vial (inventory unit = 1 vial) Store REFRIGERATED (2-8 C) Line # Date Patient's Initials Study # Kit # Quantity Dispensed or Received Balance Forward Lot Number Your Initials MOP 4 11 DEC 2013 Page 12-12

13 Drug Accountability Record PAGE OF Principal Investigator: IRB# Site: Title of Study: Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III Drug Name, Strength, & Dosage Form: 0.9% Sodium Chloride for Injection, USP 10 ml vials (preservative-free) Line # Date Patient's Initials Study # Quantity Received or Dispensed Balance Forward Lot Number Manufacturer Your Initials MOP 4 11 DEC 2013 Page 12-13

14 12.9. Catheter Irrigation (Test Article Administration Protocol) The prepared syringes containing the rt-pa or placebo and flush will be provided by the pharmacy to the appropriate study personnel for administration to the patient. The labels on the syringes must be compared with the patient s records to confirm identity. The first intraventricular injection will occur no sooner than twelve hours after the initial bleed, after randomization, and only after confirming appropriate intraventricular catheter placement by head CT. After placement of any catheter a 6 or more, hour post surgical stabilization period is required prior to first or or 12 or more hours prior to the next injection (if placed during dosing) of rt-pa. Viewing a video demonstration of the catheter injection protocol is mandatory before credentialing a center s physicians. After patient identity is confirmed, the drug will be administered as a sterile solution in preservative-free normal saline. A neurosurgeon or neurocritical care physician or their trained designee will perform intraventricular catheter injections under standard sterile technique using the process described below. Using a 3-way stopcock set-up is the ideal way to administer the drug. It allows for the catheter to drain while kept open to the transducer, measuring ICP during the injection and for the hour that the IVC is closed post injection, which is required by the protocol. The test article injection should be given as a push over a count of 20 seconds using the port closest to the head and with the least amount of drug MOP 4 11 DEC 2013 Page 12-14

15 space. Measure the length of tubing from the port of the head. The administration of the flush should follow and given as a push over a count of 20 seconds. The amount of flush administered is based on the amount of dead space in the tubing needed to be cleared. The flush should be isovolumetric with the corresponding amount of CSF withdrawn prior to test article (1ml) plus flush (up to 4 ml) injections. If you are unable to administer the flush due to high ICP, try and give at least part of the flush to account for dead space in the tubing while watching the ICP. Patient safety comes first. Document any departure from the flush administration protocol on the dosing form in the EDC system and in the medical record as source documentation Sterile Technique/Preparation k. Wash hands. l. Put on mask and sterile gloves. m. Close drainage system. n. Place sterile drape on field. o. Clean stopcock site with betadine/alcohol and allow to dry. p. Inject intraventricular catheter with syringe labeled study drug prepared by investigational pharmacy (normal saline placebo or rt-pa in a sterile solution of preservative-free normal saline) 1cc/minute q. Inject with syringe labeled flush (preservative-free normal saline) to flush catheter. r. Maintain IVC closed for 60 minutes. s. Re-open IVC after 60 minutes at the level of the head until next scheduled dose. t. Repeat study drug administration every 8 hours for up to 12 doses or until dosing endpoint, whichever comes first. a. Criteria for dosing endpoints: i. IVH volume reduced to 20% of the initial clot volume as measured on the stability CT scan (surgical endpoint) ii. 3 rd and 4 th ventricles open with return of CSF flow iii. IVH related mass effect is treated iv. Complete 12 doses of study drug v. Clinically significant re-bleeding noted on daily CT scan vi. Subject withdraws consent vii. Family withdraws life-sustaining interventions A repeat CT scan will be performed within 24 hours of the stability CT and then repeated every 24 hours until the study is completed. No more than 3 doses should be given between daily CT scans. Repeat CT scans will be performed earlier than every 12 to 24 hours if or when the treating physician determines that there is a sustained worsening or improvement of neurological condition defined as a change in 2 points on the GCS motor scale score sustained for 8 hours. Therapy will be stopped at this time if there is resolution of IVH (third and fourth ventricles are open to CSF flow), any increase in hematoma volume, any intracerebral infection or emergence of systemic bleeding disorders. If residual hematoma volume on CT scan continues to equal or exceed 20% of the initial clot volume as measured on the stability CT scan or the third and fourth ventricles remain occluded, then instillation of the next dose of study drug will occur every 8 hours until hematoma volume falls below 20% and/or 12 treatments have been performed. MOP 4 11 DEC 2013 Page 12-15