1. Pharmacist Training Revised September 2010
CLEAR III Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III
Pharmacist Training
Revised September 2010

2. AGENDA Overview Randomization Drug Supply Drug Shipment
Drug Preparation
Drug Accountability & Documentation
Unblinding Procedure
Listed below are the topics that we will cover today. A pharmacy manual will be available soon on the website.

3. OVERVIEW Multicenter, international, double-blind, randomized study
Approximately 500 patients will be enrolled across 75 study centers
Primary objective- “define the long-term effects of lysing ventricular blood clots with rt-PA on functional outcomes

4. RANDOMIZATION 1:1 (maximum of 12 doses) EVD = extraventricular drainage
EVD + rt-PA 1mg/ml every 8 hours (N=250)
EVD + PLACEBO 1ml every 8 hours (N=250)
For this study the patients are randomized 1:1 to EVD + TPA or EVD + Placebo. Both active drug and placebo are dosed every 8 hours.

5. DRUG SUPPLY
Recombinant tissue plasminogen activator (rt-PA), Alteplase (Cathflo® Activase®) 2mg vials for reconstitution
Active drug
Packaged in boxes containing 6 vials/box
Manufactured by Genentech
Storage – refrigerated 2-8° C
Provided for the study
0.9% Sodium Chloride for Injection, USP
Placebo and Flushes
Use pharmacy supply- not provided
The active drug (Cathflo Activase) for the study is provided by Genentech. Drug is packaged as Cathflo Activase 2mg vials, 6 vials per box. The Cathflo must be refrigerated at 2-8 degree celsius.
0.9% Sodium Chloride for Injection will be used as placebo for the study and for the preparation of flushes. The NaCl is not provided for the study, we are asking that pharmacy supply be used for the study.

6. Alteplase (Cathflo® Activase®)
Example of Cathflo Activase packaging.

7. Drug Shipments – USA Sites
Distributed to sites by the Investigational Drug Service (IDS), Johns Hopkins Hospital (JHH)
FedEx utilized as the courier
Shipped in multi-purpose insulated shippers with refrigerant packs
Upon arrival, drug should be unpacked immediately, examined, verified and placed in a refrigerator
A signed copy of the invoice must be faxed to the shipper
Temperature monitoring devices are not used unless requested
Drug will sent to the sites by the Investigational Drug Service at JHH. Drug is shipped in coolers with refrigerant packs utilizing FedEx as the courier. Upon arrival the drug should be unpacked immediately and placed in the medication refrigerator.

8. Drug Shipments - International
Distributed to sites by the Investigational Drug Service (IDS), Johns Hopkins Hospital (JHH) or Wellspring Clinical Services
Site will receive a “Notification of Shipment” message
Upon arrival, drug should be
unpacked immediately
examined
checked against the enclosed document (Shipping Manifest)
quarantined in a refrigerator

9. Drug Shipment (continued)
The temperature monitoring device will be secured and directions will be provided for the return of the device
Complete the “Acknowledgement of Receipt” section on the shipping document (Shipping Manifest) and return to the shipper
Temperature data will be reviewed by Qualified Pharmacist (QP)or Coordinating Center (CC)Pharmacist
QP or CC Pharmacist will approve the release the drug from quarantine
Site will receive written documentation (Final Order Release Certificate) regarding the release of the study drug

10. Drug Shipments (cont.)
DRUG CANNOT BE USED until you receive written documentation to release the drug
Initial shipments will be sent when all regulatory documentation has been received from the site
Any concerns about the drug supply should be reported to the shipper immediately
To re-order drug
Domestic -contact JHH IDS
International- process will be communicated depending upon location
Each shipment will contain an invoice documenting the contents of the shipment. After verification of the shipment the invoice must be signed and faxed to the shipper as indicated on the invoice. Temperature monitoring devices will be used to ship drug to locations (International sites) which require more that one day for delivery. Any concerns with the shipment should be communicated to the study pharmacist at JHH.

11. DRUG PREPARATION (Active)
Obtain study supply of Alteplase (Cathflo®Activase®)
Utilizing aseptic technique, reconstitute* the vial with 2.2ml Sterile Water for Inj., USP
Slight foaming is not unusual. Let the vial stand undisturbed for several minutes to allow dissipation of any large bubbles.
DO NOT shake the vial.
*Based on product package insert for Cathflo® Activase®. Each vial contains 2.2mg of Alteplase, which includes a 10% overfill
Drug will be prepared by a pharmacist or pharmacy personnel utilizing aseptic technique. The Cathflo vials are reconstituted with 2.2ml sterile water for injection. TPA is a protein and therefore should not be shaken during preparation.

12. DRUG PREPARATION Final concentration is 1 mg/ml
Draw up syringe(s) of 1 mg/ml Alteplase (Cathflo® Activase®) into 3ml sterile syringes
Cap the syringe with a sterile tip cap
Label the syringe in a blinded fashion
Expiration date for the syringe is 8 hours after reconstitution if stored at 2-30°C
Once reconstituted the final concentration is 1mg/ml therefore, syringes of 1mg/ml will be drawn up into 3ml syringes. Syringes will be labeled in a blinded fashion and expire in 8 hours.

13. DRUG PREPARATION (Placebo)
Obtain a vial of 0.9% Sodium Chloride for Injection, USP (preservative-free)
Utilizing aseptic technique, draw up 1 ml into a 3 ml sterile syringe
Cap the syringe with a sterile rubber tip cap
Label the syringe in a blinded fashion
Expiration date for the syringe is 8 hours after preparation (to match active drug syringe)
Placebo syringes of 1ml NaCL drawn up into a 3ml sterile syringe will also be prepared utilizing aseptic technique. These syringes will be labeled so that they appear to be identical to the active drug syringes. The expiration date on the syringes will also match the 8 hour expiration of the active drug.

14. DRUG PREPARATION (cont.)
Complete the drug accountability log
Used Alteplase (Cathflo® Activase®) vials can be discarded
Expiration date for the syringe is 8 hours after reconstitution/preparation if stored at 2-30°C
Drug accountability logs will be maintained for both the TPA and the placebo syringes. Used Cathflo vials can be discarded.

15. PREPARATION of FLUSHES
Obtain a 10ml vial of 0.9% Sodium Chloride Injection, preservative-free.
Utilizing aseptic technique draw 4 ml of 0.9% Sodium Chloride into a sterile 5ml syringe
Cap the syringe with a sterile tip cap
Label the syringe
Expiration of syringe is 24 hours
Each dose of study drug will be followed with up to 4ml of NaCl flush. A 5ml sterile syringe should be used for the flushes. The label on the syringe in addition to the size of the syringe will differentiate the flush syringe from the study drug syringe. Prepared flushes expire in 24 hours.

16. Can I Freeze TPA?
At time of preparation of subject’s dose, draw up the appropriate dose into a syringe
Cap syringe with a sterile tip cap
Label syringe
Store at -25° to -10°C
Discard frozen syringe(s) after 45 days*
Thaw syringe prior to dispensing
Re-label the drug for enrolled subject in a blinded fashion
*Based on USP 797 Beyond Use Dating
Reconstituted TPA can be frozen and stored in a -20C freezer for 45 days. The 45 day expiration is based on USP 797 beyond use dating. Frozen drug must be thawed for approximately 30 minutes prior to dispensing. The expiration for the thawed syringe is 8 hours.

17. DRUG ACCOUNTABILITY & DOCUMENTATION
Drug Accountability log
Document receipt and disposition of drug
Complete a log for Alteplase and placebo
Running balance must be maintained
Subject Specific log
Document preparation for an individual subject
Study drug documentation consist of the drug accountability log and the subject specific log. Documentation forms will be provided to the site pharmacists.

18. DRUG ACCOUNTABILITY
Receipt and disposition of study drug is documented on the drug accountability log
Expired vials can be destroyed on site according to your site specific policy for drug destruction
Prior to destroying the study drug on site
a copy of your site’s policy for drug disposal/destruction must to sent to the Coordinating Center (CC) Pharmacist
a drug destruction form must be completed
The DAL will be used to document all study drug activity (receipt, dispensing, returns). All unused study drug must be returned to the IDS at JHH.

19. Drug Accountability
Document the destruction of the drug on the drug accountability log
Send a copy of the completed drug destruction form to the CC Pharmacist
Send a copy of the drug accountability log to the CC Pharmacist

20. Drug Accountability Log
Example of the DAL. The form may be altered to address institution specific requirements.

21. Time of completion of product
Subject Specific Sheet
CLEAR PHASE III
SUBJECT RANDOMIZED TO: ____________________________
Frequency schedule: Every 8 Hours (total 12 doses)
Subject Name:
Investigator’s Name:
Subject #
Site #:
Date
Dose #
Time Removed from Freezer
(if applicable)
Time of completion of product
Pharmacist’s
Initials 1 2 3 4 5 6 7 8 9 10 11 12
Example of the subject specific sheet.

22. CLEAR III – Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase
RECORD OF DESTRUCTION OF INVESTIGATIONAL DRUG
Date Drug Destroyed: ____________________________
Site Number: ____________________________
Principal Investigator: ____________________________
Investigator's Address: ____________________________
Site name: ___________________________
Signature of person destroying the drug______________________________
DRUG NAME
STRENGTH
DOSAGE
FORM
NUMBER OF VIALS
Lot NUMBER
Cathflo Activase
(Alteplase)
2 mg vials
injection

23. Unblinding Procedure Site investigator must contact the Study Chairman
The Study Chairman will consult with the Medical Safety Monitor
Coordinating Center pharmacist or site pharmacist will be contacted if unblinding is necessary
Written request for unblinding will be required

24. PHARMACIST RESPONSIBILITIES
Training requirement
Adherence to study protocol
All staff preparing compounded sterile products are trained and competent (USP 797 Guidelines)
All staff preparing study drug have been trained on protocol procedures and drug preparation
Appropriate documentation is maintained
Storage and security of investigational drug
Temperature monitoring
Review of pharmacist responsibilities include…..

25. Communication
Contact the Coordinating Center Pharmacist (unblinded pharmacist) to communicate:
Any drug related concerns or occurrences
Storage deviations
Refrigerator malfunctions
Out of range temperatures
Changes in pharmacy personnel listed in the randomization system
Contact information (shipping address, phone #, fax#, addresses)

26. CLEAR III Website www.cleariii.com Pharmacy Manual Study Documents
Current protocol version
Pharmacist training presentation

27. REFERENCES CLEAR III website – www.cleariii.com
Genentech-
Alteplase (Cathflo® Activase®) product information -
USP* 797 Guidelines -
Coordinating Center (phone)
JHH- Investigational Drug Service
(phone) (fax)
Pager
*USP – United States Pharmacopeia

28. CONTACT INFORMATION
Janet Mighty, R.Ph. MBA
(Coordinating Center Pharmacist)
Investigational Drug Service
The Johns Hopkins Hospital
600 N. Wolfe Street, Carnegie 180
Baltimore, MD 21287
Phone , Fax