STANDARD OPERATING PROCEDURES (SOP): TEMPO-2 Trial Version 2.1, September 6, 2018 Dr. Shelagh Coutts and Dr. Michael Hill Confidentiality Statement The confidential information in this document is provided to you as an investigator or consultant for review by you, your staff, and the applicable Institutional Review Board/Independent Ethics Committee. Your acceptance of this document constitutes agreement that you will not disclose the information contained herein to others without written authorization from Dr. Shelagh Coutts and Dr. Michael Hill.
Transcript
STANDARD OPERATING PROCEDURES (SOP): TEMPO-2 Trial
Version 2.1, September 6, 2018
Dr. Shelagh Coutts and Dr. Michael Hill
Confidentiality Statement
The confidential information in this document is provided to you as an investigator or consultant for review by you, your staff, and the applicable Institutional Review Board/Independent Ethics Committee. Your acceptance of this document constitutes agreement that you will not disclose the information contained herein to others without written authorization from Dr. Shelagh Coutts and Dr. Michael Hill.
1. PROTOCOL AND MANUAL OF PROCEDURES: ________________________________ 4
1. PROTOCOL AND MANUAL OF PROCEDURES: The final Protocol Titled “TEMPO-2- A Randomized Controlled Trial of TNK-tPA versus Standard of Care for Minor Ischemic Stroke with Proven Occlusion” must be submitted to the local Research Ethics Board at all participating sites. Any minor changes to the protocol will be amended in the Standard Operating Procedures. This Standard Operating Procedures (SOP) will be used as a training manual for new study investigators. This SOP has been designed to help clinical investigators comply with Health Canada, ICH and GCP regulations and procedures to promote high quality research. It will document study flow to explain screening, initial evaluation, enrolment, treatment and follow up of all study subjects and to ensure they are conducted in a structured and standardized manner. It explains how data is collected, observed and recorded ensuring confidentiality of the study subject. This SOP is a dynamic working document that will be updated throughout the study to record amendments to the protocol or consent forms, and to document change to procedures. If the protocol is modified, the SOP will be updated to reflect these changes. 2. STAFF ROSTER 2.1 TEMPO-2 COORDINATING CENTRE CONTACT INFORMATION
2.2 EMERGENCY CONTACTS Please note that either: Dr. Shelagh Coutts, or Dr. Michael Hill will be the On Call Medical Monitor regarding any questions about the following topics:
• randomizing a subject
• reporting a serious adverse event or a bleeding event
• protocol questions
• eligibility questions
• reporting protocol deviations
All sites will be able to contact an on-call physician at all times. Please call one of the above physicians on the number listed above. 2.3 STUDY CONDUCT AND INTEGRITY Please note the University of Calgary (U of C) site will serve as the Coordinating Centre and overall sponsor. The overall sponsor for regulatory purposes is the University of Calgary. Sub-sponsors may be designated for specific regions of the world. Dr. Shelagh Coutts will be the Sponsor Investigator (SI) for the trial. The SI and/or Dr. Michael Hill or Carol Kenney (delegated by the SI) will manage the following:
• Keep all participating hospital sites informed of study status and issues.
• Fulfill regulatory responsibilities of the clinical trial sponsor in each jurisdiction, protocol Amendments or study changes.
• Fulfill responsibilities of the clinical trial sponsor to reporting to other regulatory agencies.
• Proper verification and maintenance of study documentation
• Source monitoring at clinical sites
• Review and implementation of any recommended changes from the DSMB
• Review of Adverse Events and Protocol Violations
• Ensuring proper closeout of study
• Study Drug Accountability for clinical sites- if applicable
3.0 TRAINING PLAN All sites will have a Site Initiation done either in person or via teleconference/webinar by Drs. Coutts or Hill or Carol Kenney. The Protocol, SOP, GCP/ICH guidelines, study drug administration and dosing, the CRF and Electronic Database, the Study Manger and Image Transfer will be reviewed
with the study staff. Training will be documented in the Training log in the Electronic Regulatory Binder (Study Manager). Inclusion and Exclusion screening cards will be given to the study staff if requested or used at the site. The study sites may be visited several times by the Coordinating Centre personnel throughout the duration of the study. Sites will be visited for retraining if there are issues with Protocol Compliance or continual problems conducting the study. For training of informed consent and study drug administration, please access the following website: http://ucalgary.ca/dcns/research/tempo-2/tempo-2-documents
Username = TEMPO2 password = Stroke33
A certificate will be generated once you have completed both training segments and will be uploaded into the TEMPO2 Study Manager. 4.0 PHARMACY/STUDY DRUG 4.1 GENERAL INFORMATION The Investigator may delegate some or all of the investigational product duties to a Pharmacist, Coordinator or another appropriate individual who is under the Investigator’s supervision. The duties that may be assigned include:
• Appropriate storage of all trial medications
• Medication accountability and reconciliation
• Investigational medication use in accordance with the protocol
• Provide proper instructions of medication use for all the subjects
4.2 INVESTIGATIONAL DRUG The LOT number and expiry date of the study drug (Tenecteplase) are identified on the side of the box of tenecteplase. This information is recorded in the CRF and database for future reference if
needed. The trade name for tenecteplase is TNKase™ in North America and Metalyse™ in Europe
and Australasia. The antiplatelet used in the Control arm will be administered in Emergency and are considered “Standard of Care”, therefore no expiry date or Lot number will be recorded. 4.3 STORAGE AND STABILITY
TNKase™ (or Metalyse™) is supplied as a sterile, lyophilized powder in a 50mg, glass (20cc) vial
under partial vacuum. Reconstitution should occur based on the package insert.
There are different sized vials of TNKase™ (or Metalyse™) available in different countries. In
Canada for example 50mg vials are available. Each 50mg vial of TNKase™ (or Metalyse™) is
packaged with one 10ml vial of Sterile Water for Injection for reconstitution. TNKase™ (or
Metalyse™) (tenecteplase, TNK-tPA) lyophilized must be stored at controlled room temperature (2-
30°C), not to exceed 30°C or under refrigeration (2°C - 8°C). Do not use TNKase™ (or Metalyse™)
beyond the expiration date stamped on the vial. Unused reconstituted TNKase™ (or Metalyse™) (in
the vial) may be stored at 2°C - 8°C and used within 8 hours. After that time, any unused portion of the reconstituted material should not be used. For other sizes follow the reconstitution instructions included with the drug.
For sites using “off the shelf TNKase™ (or Metalyse™)” in Emergency, no temperature monitoring
will occur, as the drug is considered to be standard of care for clinical use. This also applies to the anti-platelet agents that will be used in the Control Arm. Please adhere to local Country Regulations
in regards to temperature monitoring of “off the shelf TNKase™ (or Metalyse™”). The sponsor does
not mandate temperature monitoring of the off the shelf TNKase™ (or Metalyse™”. In sites where the study medication is stored separately we will defer to local policies and procedures as to whether temperature monitoring/ labelling is required.
4.4 ACCOUNTABILITY
All vials of TNKase™ (or Metalyse™) will have an assigned Lot number and Vial number. As per
ICH/GCP guidelines, this information will be recorded and maintained for the duration of the trial. This will be recorded in the eCRF (plate 013). 4.5 STUDY DRUG ADMINISTRATION
All patients will be treated with intravenous TNKase™ (or Metalyse™) using their estimated body
weight to calculate a weight-adjusted dose. An estimated weight will be used, as it may not be feasible to obtain an actual measurement in the emergency department (subject can`t stand safely, time restraints, etc.). If an exact weight of the subject is obtainable, please use this weight.
TNKase™ (or Metalyse™) must be reconstituted by a licensed RN or physician or pharmacist signed
onto the study and listed on the Delegation of Authority log. Reconstitution of 50mg of tenecteplase in 10 ml of sterile water results in a solution concentration of 5mg/ml. For other sizes of tenecteplase follow the reconstitution instructions included with the drug. The dose is 0.25 mg/kg or 0.05ml/kg. A dosing table is provided below and on the TEMPO2 website. Treatment will be administered as a single intravenous bolus over 10 seconds, given by the treating Investigator, who must also be signed onto the trial and documented in the Delegation of Authority log. A training video has been created for all investigational staff to observe prior to administering
TNKase™ (or Metalyse™). A certificate will be generated after the video has been observed and
filed in the Regulatory Binder, as well as uploaded into the TEMPO2 Study Manager.
4.6 PRODUCT MONOGRAPH Health Canada requirements state that all Canadian sites have access and awareness of the latest Canadian Product Monograph. Please refer to this product monograph for information regarding TNKase™. The link below is provided for convenience: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/databasdon/index-eng.php Tenetecplase DIN: 02244826 Other countries participating in the trial have access to their local product monograph. 4.7 DOSE CALCULATION Subject’s weight (kg) x DOSE 0.25mg/kg = X (ml) (see chart below)
4.9 RECONSTITUTION The information described below is for the 50mg vial of TNK. The principle is the same for the 30mg and 40mg vials except the included syringes are 6ml and 8ml respectively. The B-D® 10cc Syringe with TwinPak® Dual Cannula Device
1. Remove the shield assembly from the supplied B-D® 10 cc Syringe with TwinPak® Dual Cannula Device (see figure) and aseptically withdraw 10 mL of Sterile Water for Injection (SWFI), USP from the supplied diluent vial using the red hub cannula syringe filling device. Do not use Bacteriostatic Water for Injection, USP. Note: Do not discard the shield assembly.
2. Inject the entire contents of the syringe (10 mL) into the TNKase™ (Metalyse™) vial directing the diluent stream into the powder. Slight foaming upon reconstitution is not unusual; any large bubbles will dissipate if the product is allowed to stand undisturbed for several minutes. 3. Gently swirl until contents are completely dissolved. Do not shake. The reconstituted preparation
results in a colourless to pale yellow transparent solution containing TNKase™ (Metalyse™) at 5 mg/mL at a pH of approximately 7.3. The osmolality of this solution is approximately 290mOsm/kg.
4. Determine the appropriate dose of TNKase™ (Metalyse™) (see Dose Information Table) and withdraw this volume (in milliliters) from the reconstituted vial with the syringe. Any unused solution should be discarded.
5. Once the appropriate dose of TNKase™ (Metalyse™) is drawn into the syringe, stand the shield vertically on a flat surface (with green side down) and passively recap the red hub cannula. 6. Remove the entire shield assembly, including the red hub cannula, by twisting counterclockwise. Note: The shield assembly also contains the clear-ended blunt plastic cannula; retain for split septum intravenous (IV) access 4.10 ADMINISTRATION 1. The product should be visually inspected prior to administration for particulate matter and
discoloration. TNKase™ (Metalyse™) may be administered as reconstituted at 5 mg/ml.
2. Precipitation may occur when TNKase™ (Metalyse™) is administered in an IV line containing dextrose. Dextrose containing lines should be flushed with a saline containing solution prior to and
following single bolus administration of TNKase™ (Metalyse™).
3. Reconstituted TNKase™ (Metalyse™) should be administered as a single IV bolus over 10 seconds.
4. Because TNKase™ (Metalyse™) contains no antibacterial preservatives, it should be reconstituted
immediately before use. If the reconstituted TNKase™ (Metalyse™) is not used immediately,
refrigerate the TNKase™ (Metalyse™) vial at 2 – 8°C and use within 8 hours. 5. Although the supplied syringe is compatible with a conventional needle, this syringe is designed to be used with needleless IV systems. From the information below, follow the instructions applicable to the IV system in use.
Split septum IV system:
• Remove the green cap.
• Attach the clear-ended blunt plastic cannula to the syringe.
• Remove the shield and use the blunt plastic cannula to access the split septum injection port
• Because the blunt plastic cannula has two side ports, air or fluid expelled through the cannula will exit in two sideways directions; direct away from face or mucous membranes.
Luer-Lok® system:
• Connect syringe directly to IV port.
Conventional needle (not supplied in this kit):
• Attach a large bore needle, e. g18 gauge, to the syringe's universal luer- Lok®.
6. Dispose of the syringe, cannula and shield per established procedures. 4.11 OVERDOSAGE Single doses greater than 50 mg (10,000 units) have not been tested. The total dose should be based on patient weight, not to exceed 50 mg (see DOSAGE CHART AND ADMINISTRATION in Section 4.7, and 4.8). There is a maximum of 50mg in any given vial of study drug; no subject should ever receive 50mg of study drug. Any patients receiving greater than the recommended dosage should be carefully monitored. The coordinating centre must be notified immediately if this situation arises. The SI will also notify Health Canada and other regulatory bodies as needed of any drug overdosing. Bleeding complications, notably Intracranial Hemorrhage (ICH), are the most important adverse events associated with TNKase™ (tenecteplase), as with other thrombolytics. If bleeding occurs, standard medical management should be implemented. Bleeding events must also be reported immediately to the coordinating centre by completing the SAE form in the eCRF database. 4.12 STUDY DRUG DOSE VERIFICATION The patients’ estimated weight and correct dosage must be verified by the RN/physician/pharmacist mixing the study drug, as well as the physician administering the study drug. If only the treating Investigator is present and is enrolling the patient, please have an Emergency RN or Physician verify the correct dosage. The rationale for dose verification is to decrease the likelihood or possibility of any overdosing or study drug dosing errors. Please record the Investigator who administered the study drug. The Investigator may allow a delegated resident or fellow not involved in the trial to administer the study drug under their supervision.
5.0 RECRUITMENT PLAN All eligible patients for the TEMPO-2 trial will be seen in the Emergency department and screened by the treating Investigator and Coordinator. Patients arriving/transferred from surrounding hospitals may have a repeat CT and CTA if the patient still meets Inclusion / Exclusion criteria.
5.1 STUDY FLOW
24h Serum creatinine
LEGEND
No END
Patient presents to ER
Yes
Randomize
Patient sign ICF
AdministerTNK/Control
Day 5 AssessmentOR
Discharge*
Day 90 Assessment
Baseline Visit
Randomization output
ImagingCT-CTA
Imaging4-8hr CTA
Imaging24hr CT/
MR
END
Patient eligible?Signed ICF
CRF BL Data
CRFD5/DC
CRFsD90EOS
CRF Treatment Assignment
= Patient interaction/ Visit
= CRF Data output
= Imaging event
= Source data output – Hard copy
*Assessment to be performed at Day 5 OR at time of discharge – WHICHEVER IS SOONER
**Assessor must be blinded to treatment arm**
CRF24hr Data
6.0 SCREENING AND ELIGIBILTY CRITERIA All Inclusion and Exclusion criteria must be met to enroll a patient. Please refer to the Protocol. For all imaging MRI/MRA can be substituted for CT/CTA. If a patient presents to your site from another location in the same country, it may be possible for another participating site to follow up this patient in the future. Please call one of the TEMPO-2 On-Call Investigators to inquire if this would be feasible. Alternatively, telephone follow up is an option if all other options have been considered. 6.1 SCREENING LOGS No screening logs will be completed or collected for this study. 6.2 STUDY SUBJECT ID ASSIGNMENT The Study ID will consist of the site number and the subject number. The patient number is assigned sequentially beginning with 01. Up to 1274 patients will be enrolled at participating sites throughout the world. If Informed Consent is obtained, but the patient is not randomized, they will not be considered to be enrolled, although it is requested to please keep the Informed Consent on file at your site. A patient is considered enrolled in the study the moment the randomization assignment has been received from the on-line system. The randomization assignment will be time-stamped by the server. The internet server will be synchronized to accurate time, minimally on a weekly basis. Study drug (both arms: active treatment or control) should be administered immediately after randomization assignment – i.e. with-in 5 minutes. If there is a delay i.e. due to elevated blood pressure then this should be documented. 7.0 CONSENT Definition: Informed consent is a process that involves:
• providing patients with adequate information concerning the study procedures and scope
• providing adequate opportunity for an individual to consider all available options
• responding to individuals’ questions and concerns
• ensuring that each individual understands all information provided
• obtaining the individual's written voluntary consent to participate Additional items that should be included in an informed consent document include:
• complete disclosure of any appropriate alternative procedures, risks, benefits and any risks/benefits of the alternatives
• disclosure of the extent of confidentiality that will be maintained
• statement of compensation and/or medical treatment available if injury occurs
• name, address, and telephone number of the Principal Investigator 7.1 INFORMED CONSENT PROCESS When study physicians/investigators encounter a patient who appears to meet TEMPO-2 inclusion/exclusion criteria, the enrolling physician/investigator, along with the coordinator, will describe the study, they will ask the patient to read the informed consent form, and evaluate patient competency to provide consent. If the patient is competent to consent and wishes to participate, the patient and the enrolling physician or coordinator, will both sign the informed consent document. A witness may be present when the patient signs the informed consent if required by the local ethics
committee. If the patient is determined not to be competent (not oriented to time and place or not able to understand key aspects of the trial and its procedures, potential risks, potential benefits, and duration of participation), the enrolling physician or coordinator will try to reach a legally authorized representative, provide them with a written informed consent, and elicit consent, (if surrogate consent is approved by the local ethics committee). If a patient is not competent and no legally authorized representative can be reached, the patient may not be enrolled in the TEMPO-2 trial. No telephone consent or Waiver of consent will be granted unless this is approved by the local ethics committee. All participating sites must follow their Research Ethics Board requirements and guidelines in obtaining both patient and surrogate consent. Date and time of when the consent was obtained must be documented on the Signature page of the Informed Consent form. Remote Monitoring will be performed to ensure that the time of Informed Consent was obtained prior to randomization. The patient or surrogate must try to complete the date and time of consent, as well as their printed name and signature. The International Committee on Harmonization (ICH) Good Clinical Practice (GCP) guidelines requires that the subject or legal representative receive a copy of the signed and dated informed consent form. Additionally, the investigator must maintain a signed copy of the informed consent document for each subject in the study. The source documents should indicate that the informed consent form was signed, along with the date of signing. This should be documented in the patient’s hospital chart or the patient’s CRF. If there is a change in any of the study procedures that may affect the patient, the informed consent document must be revised and again approved by the REB. Any patients enrolled in the study prior to such changes must sign the amended consent form. The revised consent form must also be reviewed and approved by the Coordinating Centre prior to submission to your local REB. The Informed Consent forms have officially been translated to French, Spanish and German; a certificate of translation is available to all REB’s for verification of translation. Please refer to Appendix 2.0 for a Template of the English Patient Consent Form. In sites where approved by the local ethics committee there is a section on the consent form allowing the signature page of the consent form to be securely uploaded for central review. Signature, date and time etc. will then be checked centrally for accuracy.
8.0 ENROLLMENT NOTIFICATION A patient will be considered to be enrolled once they have been randomized. Notification of patient enrollment will be emailed to the TEMPO-2 Coordinating Centre, as well as all participating sites. The auto-generated randomization form should be printed out and maintained in the subject study-binder.
8.1 TIMELINE AND VISIT SCHEDULE Time zero is the time of randomization, defined by the randomization server. Unless otherwise stated all times are measured from this time. Randomization occurs via the study manager. Site, sex, month of birth, year of birth, time of onset and baseline NIHSS, estimated weight is required for randomization. This data will be auto populated into iDatafax. If there are errors subsequently discovered in what was entered in then contact the central coordinating site to discuss any changes that need to occur.
Time of onset is measured do the nearest 5 minutes if time. If required you can manually enter another number if the time does not end in a 0 or a 5. Time of onset is the last time seen well. Baseline NIHSS is the NIHSS measured just before randomization. The baseline assessments will be performed as standard of care. The times of the ECG, emergency blood work / labs as well as the physical and neurological assessments may be performed prior to obtaining Informed Consent. Informed consent must be obtained prior to randomization. Results of the baseline blood work do not need to be available to go ahead with treatment if this is the usual protocol for thrombolysis in the local institution. The patient must receive tenecteplase or control within 90 minutes of the first slice of the CT scan. Measurement will be from the time-stamped CT scan and the randomization server. There is a 10-minute allowance in all times to compensate for time differences of clocks, watches, CT scanners etc. Therefore, up to 100 minutes has been allowed without a protocol violation determination. The ECG may be performed up to 6 hours after the randomization. Guidance on ‘Resetting’ the clock for enrolment in TEMPO-2 using repeat imaging
1. TEMPO-2 allows for enrolment into the study when study drug can be administered within 90 minutes of the first slice of the qualifying baseline CT brain scan. When, that time has elapsed it is acceptable to repeat the non-contrast CT brain scan only to ‘reset’ the clock for enrolment. This second scan then becomes the qualifying CT brain scan. To avoid extra radiation and contrast dye exposure, the CTA is not required to be repeated. This is only acceptable when the neurological examination is unchanged from when the original CTA was completed. If the patient has improved or worsened then the CTA needs to be repeated after 90 minutes have elapsed.
2. Allowing for the above, all subjects must still be enrolled within 12 hours of stroke onset (defined as the last known well time).
3. The intention of the above rule is to identify substantial ischemic change that may have evolved since the time of the initial imaging. If that is discovered, then the patient should NOT be enrolled in the study since they will now have fulfilled an exclusion criterion. Thus, the rule is founded in patient safety.
4. However, the rule is also intended to apply to situations where the time has ‘just’ elapsed and not after many hours have elapsed. In the clinical situation of minor stroke/TIA, it is unknown how long the non-contrast brain CT scan and the CTA are durable and predict outcome, treatment safety or treatment effect. It is unknown how often patients with minor stroke and proven occlusion will spontaneously recanalize and on what timeframe.
Guidance: If greater than 3 hours have elapsed since the first slice baseline brain CT scan, then we
recommend reconsidering the entire imaging protocol (CT and CTA) to re-determine eligibility. In
this situation, please call the medical monitor to discuss the case prior to enrolment.
4-8hour Follow up CTA The 4-8 hour CTA of the circle of Willis will be completed based on the time from drug administration (tenecteplase or control). The patients’ baseline renal function must have an eGFR >40ml/mol/l to perform the follow-up CTA. If the patient is enrolled based on a CTP abnormality with no corresponding CTA abnormality then the repeat CTA does not need completed. If a patient had an allergic reaction to contrast then the CTA is not repeated. Day 1 will be performed at 24 (+/- 8 hours) hours from randomization. Day 5 or discharge assessments will be performed anytime on day 5 or day of discharge. If the subject is discharged prior to Day 5, the follow up assessments will be performed at the time of discharge.
The Day 90 follow-up visit will be completed with a date range of 76-104 days from randomization. The End of Study form will be completed at the same time as the Day 90 form or the last time point when the patient was assessed as part of the trial. The PI will sign off electronically in the eCRF once the patient has completed their End of Study Form. The electronic signature does not indicate that the data is complete, rather acknowledging that the patient has completed their participation in the trial and aware of any SAE’s.
9.1 SCHEDULE OF ASSESSMENTS CHART Baseline 4-8 hour Day 1 Day 5 or D/C Day 90
Informed consent X History and examination X Weight X˟ X± X± X±
NIHSS X X X X
mRS X X
EuroQol X
Lawton IADL X CT head or MRI** X X
CTA COW** X X Full Emergency Stroke Labs X
Creatinine X
ECG X
Adverse Event X X X Serious Adverse events X X X X Prior medications X
Con Meds X X X X X only with SAE *Study Drug must be given within 90 (+10) minutes from the first slice of the CT. ** All imaging completed in the first 48 hours should be transmitted to Calgary for Central review. *Patient weight used at baseline may be an estimated weight used for dosing. ± Actual weight must be performed once by Day 5 or Discharge and recorded, not necessary to be done at all time points.
10. PATIENT MANAGEMENT AND FOLLOW UP 10.1. PATIENT MANAGEMENT
• All patients will have standard of care medical management on an acute stroke unit.
• Admission to a monitored unit for 24 hours is required if the patient is randomized to the
TNKase™ (Metalyse™) (tenecteplase) arm.
• Vital signs will be the same requirement as a patient receiving tPA, for patients
randomized to the tenecteplase (TNKase™/Metalyse™) arm.
• Follow-up imaging is required at 4-8 hours (CTA) post drug administration, as well as at 24 hours (+/- 8 hours) from randomization with CT or MR. Use of MR will be encouraged.
• Follow-up imaging after 24 hours is at the discretion of the treating investigator for any patients with neurologic deterioration to rule out intracranial hemorrhage
• No antiplatelet agents or other antithrombotic medicines should be given within the first 24 hours (+/-8h) in patients randomized to the tenecteplase arm.
10.2. FOLLOW-UP EVALUATIONS
• Patients will be assessed at 24h or at any time of neurological deterioration.
• Patients will also be assessed at Day 5 or Discharge, whichever is sooner.
• The 90 day evaluations MUST be completed by study personnel blinded to the subject and their initial hospital course in the first 48 hours. The definition of a blinded assessor is any TEMPO2 personnel not involved in the patients care in the first 48 hours. This means that the individual assessing the patient does not know which arm the patient was randomized to or the recanalization status on the follow up CTA. The blinded assessors must be trained in the mRS and NIHSS and hold valid certification. A form must be uploaded the database that confirms that the person completing the assessment is blinded.
• The day 90 evaluations will be done in person. If the patient cannot return in person for follow up, please ensure that all routes to contact the subject and arrange for in-person evaluation have been exhausted. The TEMPO-2 Coordinating Centre will assist you for suggestions on locating the subject. As a last resort, telephone follow-up assessment will be accepted and the mRS may be conducted over the phone with the patient or family member.
10.3. STANDARD OF CARE
• All patients should have stroke unit care: o DVT prophylaxis for non-ambulatory patients o Swallowing assessments and management to prevent aspiration pneumonia o Management of fever, elevated serum glucose o Careful management of blood pressure
• All patients should have excellent stroke prevention therapy. This includes investigation to understand the mechanism of stroke. In particular, we expect careful investigation of the carotid artery system for atherosclerotic carotid artery disease, and of the heart and aortic arch for cardio embolic sources.
• Patients with relevant carotid artery stenosis should undergo prompt revascularization.
• Patients with a cardio embolic source requiring anticoagulation should be anti-coagulated prior to leaving hospital.
• Careful stroke prevention therapy is critical for maintaining outcomes out to 3 months. We expect most patients will have good outcomes but we do not want good work done in the first 24h to be undone by recurrent stroke at 1 month.
• Patients, who require it, should have appropriate and intensive rehabilitation therapy.
11.0 PATIENT RETENTION Every effort should be made to retain study subjects without being coercive. Avoidance of loss to follow up or withdrawal of consent is a high priority in this trial, as study endpoints and outcomes are dependent on collecting all follow up visit data. Thus, it is important that several contacts should be identified (home, work, mobile phone numbers, address, email, contact info of next of kin) during the screening process. If the patient is unable or unwilling to return for the 3-month follow-up, please perform the follow-up by telephone. Loss to follow up patients will negatively impact the study outcome. Every effort must be made to prevent any loss to follow up patients. Please contact the Coordinating Centre for assistance; if you experience any difficulty with patient follow up. A protocol waiver must be requested if the patient will be seen outside of the allotted time window. If no waiver is requested, and the patient is seen outside of the allotted window, this will be considered a Protocol Deviation. 12.0 CASE REPORT FORMS 12.1. OVERVIEW OF INSTRUCTIONS FOR COMPLETION All study patient data reported must be documented on the Case Report Form. The case report form becomes part of the patient’s onsite study records. The SI (Sponsor Investigator), the Study Monitor and Local Regulatory bodies will have access to the Case Report Form.
12.2. SOURCE DOCUMENTATION Source documents are any documents (electronic or written) on which study data are recorded for the first time. Source documents include, but are not limited to, electronic and written medical records (inpatient and outpatient); worksheets developed for study use, standardized test forms and laboratory reports. The source documents are necessary to validate the information that has been entered into eCRF. The source documents also will need to be readily available during site monitoring visits and may be requested to be uploaded into the database (de-identified). Because this is a hospital based study that begins in the Emergency Department, source documents will include electronic or written: -hospital Emergency department record -hospital in-patient medical record -clinic encounter documentation at follow-up -diagnostic test results (imaging, laboratory) obtained during the study period -rehabilitation ward/hospital medical records -case workbook for each subject 12.3. INSTRUCTIONS FOR COMPLETION Each form in the CRF has individual instructions if appropriate. A HELP icon will be present on the top right corner of each page in iDatafax. This icon will display detailed instructions for completing the CRF page. More detailed instructions for completing the CRF are provided in APPENDIX 7.0. Please see APPENDIX 8.0 for the eCRF Pages that are in the database.
12.4. SIGNATURE PAGE OF INFORMED CONSENT UPLOAD/REVIEW Remote monitoring of the Informed Consent form will be done by designated personnel at the
TEMPO-2 Coordinating Centre. The purpose of remote monitoring of the signature page of the
Informed Consent is to ensure:
• The consent form was signed by the patient or surrogate
• Date and time fields were completed by the patient (ensuring that the patient has completed
these details themselves)
• Investigator name- ensuring that the consent was obtained by the appropriate delegated
person
• Randomization time and date- ensuring the time of consent is prior to the randomization time
(found on Plate 1)
• Witness (if applicable)- signed by witness in an acceptable time frame
• Consent form is on headed paper, correct version used
Site personnel will upload the signature page of the Informed Consent form into the TEMPO-2 Study
Manager site. Local Ethics Board /REB approval must be obtained. The Informed Consent form will
have a statement indicating to the patient/family the Signature page will be reviewed by the Sponsor.
If the Local Ethics Board /REB does not approve the signature page of the consent upload, the
sponsor requests sites to redact the name and signature to maintain confidentiality and upload into
the TEMPO-2 Study Manager Site. The time and date of informed consent can be monitored and
reviewed to ensure correct enrolment procedures were followed.
The Tempo2 web application is a secure website. The files are encrypted on the server. Consent
files uploaded from the Tempo2 website are securely encrypted at rest.
13.0 ADVERSE EVENT REPORTING Definition: Adverse Event (AE): An AE is any unfavorable and unintended diagnosis, sign (including an abnormal laboratory finding), symptom, or disease temporarily associated with the study intervention, whether or not related to the intervention. AEs, which may be mild, moderate, or severe, include new events not present during the pre-intervention period or events that were present during the pre-intervention period but have increased in severity. The site investigator is responsible for making the initial determination as to whether the AE is possibly, probably, or definitely related to the study intervention. Note: Unchanged, chronic medical conditions consistent with natural disease progression are NOT AEs and should not be recorded on AE pages of the CRF unless there is an exacerbation of a chronic condition. These medical conditions should be adequately documented on the appropriate page of the CRF (medical history and/or physical examination). Adverse Events (AEs) encountered during treatment and post-treatment periods will be recorded on the appropriate AE pages of the Case Report Form (CRF). For this protocol, all simple Adverse Events will be collected from the time of Study Drug administration to the Day 5 visit only. If an Adverse event is ongoing at day 5 then this needs to be reassessed at day 90 to see if it has resolved or if it is still ongoing. Any Serious Adverse Events will
be recorded out to the Day 90 visit. An Adverse Event form will be completed for all SAEs and then additional information will be collected on a SAE form if a SAE occurs. Managing Simple Adverse Events: 1. Use all possible resources (your knowledge, investigator and team, treating medical team) to
classify adverse events as a diagnosis. For example, report pneumonia as a single AE, rather than shortness of breath and tachypnea as two separate “symptom-defined” AEs.
2. Report isolated diagnostic test results as AEs selectively according to clinical judgment. Laboratories (blood, urine, other body fluid) that are abnormal may be adverse events. However, this does NOT apply to all out of range results. Laboratory results are only an adverse event intrinsically when they require a change in management or intervention, even if that change means more careful observation. For example, a serum Na of 133 mM is out of range, but not is associated with any abnormality or any action; it is simply part of the normal course of being sick in the hospital with a stroke. Further, a serum Na of 122 mM associated with a new seizure, is an adverse event, but can be reported as a single event as a “seizure due to low serum Na”. Finally, a serum Na of 122 mM without symptoms will require a change in management and therefore can be reported as a single AE of “hyponatremia”. Imaging results follow the same paradigm as the laboratory results.
3. Asymptomatic hemorrhagic transformation is reported as an AE. If there is no repeat scan completed then we suggest using a date of 7 days after the initial scan showing the hemorrhage for the resolution of the AE.
Serious Adverse Event (SAE) - A SAE is any untoward medical occurrence that results in death, is life-threatening, requires or prolongs hospitalization, causes persistent or significant disability/incapacity, results in congenital anomalies/birth defects, or, in the opinion of the investigators, represents other significant hazards or potentially serious harm to research subjects or others. All SAE`s will be collected for the full study period – randomization to Day 90 visit. 13.2 SAE REPORTING All serious adverse events (both expected and unexpected) occurring during the study, whether observed by study staff or reported by the patient, must be recorded on the Adverse Event for with additional information on the Serious Adverse Event (SAE) form in the CRF and Database. All SAEs should be reported to the TEMPO-2 Clinical Coordinating Centre within 24 hours of notification of the event by entering the SAE in the database (iDatafax). The database will notify both Dr. Coutts and Dr. Michael Hill that a SAE has been reported. The SAE will be reviewed and if necessary, the reporting site may be contacted for further information. All SAEs require a time of onset and of ending. This may be difficult at times, but a reasonable estimate of the time of onset or end of the SAE is required for all SAEs. All SAEs will be adjudicated by independent Safety Monitors. The TEMPO-2 Coordinating Centre is required to report selected SAE’s to Health Canada or other regulatory authorities. Health Canada must be notified of all serious adverse events that are both judged to be related to the use of study drug and that are unexpected. SAE reporting to your local research ethics board will be dependent upon each research ethics board reporting requirements. If research ethics board reporting of a SAE is a local requirement, please send the research ethics board report to the TEMPO-2 Clinical Coordinating Centre, as well as the acknowledgment letter from your local research ethics board in regards to the reported SAE. Expected tenecteplase serious adverse outcome events are as follows:
(i) Symptomatic intracranial hemorrhage defined as new intracranial hemorrhage (ICH, SAH, IVH, and SDH) associated with clinical evidence of neurological worsening, in which, the hemorrhage is judged to be the most important cause of the neurological worsening. Clinical worsening will be guided by the NIHSS score change of a minimum of 2 or more points different from baseline.
(ii) Major extracranial hemorrhage defined as life threatening, resulting in hemodynamic compromise or hypovolemic shock, requiring inotropic support or other means to maintain cardiac output, requiring blood transfusion of more than 2 units of packed red blood cells, or associated with a fall in hemoglobin greater than or equal to 5 g/L.
(iii) Life-threatening angioedema defined as severe airway obstruction requiring intubation. (iv) Life-threatening thrombolysis associated hypotension defined as a drop in blood pressure
that requires inotropic support. Outcome events are also reported as Serious Adverse Events. For example: a patient with a new TIA with DWI positive lesion and patient is not admitted. Stroke progression or recurrent stroke will be reported as a SAE. If an SAE is rated as resolved with sequelae then the AE associated with this event should be assessed as resolved with the same date as the SAE. 14.0 LABORATORY SPECIMEN MANAGEMENT All subjects will have the following baseline blood tests completed locally prior to study enrollment and assessed for abnormal and clinical significance:
• Coagulation: INR, aPTT A pregnancy test (urine or blood) will be completed in women of childbearing age potential. The test must be negative for participation in the trial. This must be documented in the source documents. A copy of local laboratory certification and normal ranges of lab values should be filed in the site’s electronic Regulatory Binder. 15.0 MONITORING VISITS/LOCAL REGULATORY BODY AUDITS Sites will be monitored for source verification and study compliance. Sites will undergo a site initiation visit with Drs. Coutts/Hill in person or via teleconference/webinar. All local regulatory bodies are privy to all study documents and may perform an audit at any time during the trial. Site monitoring will take place through periodic site visits conducted during the course of the study. The frequency of visits depends upon the number of subjects enrolled. Risk based monitoring will take place at each site. Quality Control and central review will also occur and conducted by posting queries in the database for any missing information or incorrect data entered. The purposes of monitoring visits are to:
• assure the rights and safety of subjects
• confirm that study conduct follows the guidelines of Good Clinical Practice (GCP)
• assure maintenance of required documents
• verify adherence to the protocol
• monitor the quality of data collected
• assure accurate reporting and documentation of all adverse events
During the monitoring visits, the data recorded on the study forms are reviewed and verified against source documents and/or the eCRF base to assure:
• informed consent has been obtained and documented
• adverse events have been identified and recorded
• the information recorded on the forms is complete and accurate
• there are no omissions in the reports of specific data elements
• missing examinations are indicated on the forms
• subject disposition at study exit is accurately recorded
Site investigators must allow the clinical monitor access to all study documents, including informed consent forms, drug accountability records, and source documents, including pertinent hospital or medical records. Once the site visit is complete, a site monitoring report will be drafted to provide feedback regarding any problems or issues that may have been uncovered during the visit. The TEMPO-2 Coordinating Centre will follow up with the sites to ensure that all issues have been resolved. 16.0 PROTOCOL VIOLATIONS/ DEVIATIONS Sites are expected to adhere to the protocol, minimize subject non-compliance and enhance subject retention. Comprehensive training, early review of the data, and routine communications with the sites will help to minimize protocol deviations. Protocol Violations/ Deviations will be recorded by the sites in the eCRF. These violations will be tracked in the eCRF. Study sites should report a violation within 24 hours of occurrence or as soon as it is discovered to both their Ethics Research Board, (if required) as well as the TEMPO-2 Coordinating Centre. In addition, if the site monitor discovers any of these violations during a monitoring visit, they should notify the SI’s of the occurrence in writing. The DSMB will also be notified of all Protocol Violations and Deviations. There may be rational clinical reasons for an occasional violation. A site with serious continual problems will be at risk of being terminated from participating in the trial. Protocol violations include but are not limited to the following:
• enrollment of an ineligible subject
• failure to obtain informed consent
• entering a subject into another study
• failure to keep IRB approval up to date
• wrong treatment (overdose) administered to subject 17.0 DSMB MONITORING- DATA AND SAFETY MONITORING The DSMB members have no direct or indirect financial interest in TEMPO-2. The members also have no Conflict of Interest by serving on the board. The roles and responsibilities of the DSMB include the following: monitor study quality, safety of subjects, and efficacy. Monitoring performance of the study usually includes reviewing:
• subject recruitment
• flow of data
• quality control of the data
• adequacy of medical monitoring
• adverse event reporting
• adherence to protocol
• appropriateness of protocol changes with regard to scientific integrity
The DSMB members will review safety reports after 100 patients have been enrolled. The DSMB will also meet after 400 patients have been enrolled as well as at the interim analysis (~850 patients). The DSMB will review any serious safety events that are possibly/probably/definitely related to study drug at the discretion of the treating physician. All of the data will be reviewed and the DSMB will deem if it will be safe to progress until 1274 patients have been enrolled. 18.0 RETENTION OF STUDY DOCUMENTS As per Health Canada Regulations, because this study is being conducted under a Health Canada CTA, all study documents must be stored and archived for 25 years. The location and address of the storage facility used for participating sites will be sent to the TEMPO-2 Coordinating Centre. Regulatory bodies outside of Canada will have varying archiving or retention requirements. Each site will at minimum adhere to the Health Canada retention regulations or longer if required by their own country requirements.
19.0 DATA MANAGEMENT The study will make use of the iDatafax platform for electronic document capture to manage study data. Randomization will be managed by a central server at the University of Calgary. The electronic study regulatory binder will be similarly managed at the University of Calgary. These services will be provided by the University of Calgary Clinical Research Unit (CRU).
• Data Tracking - The CRU will provide to the TEMPO-2 Coordinating Centre the status of subject enrollment and the number of forms completed at the sites.
• Data Entry - The CRU has designed the eCRF to ensure that is easy to use and minimizes data entry errors.
• Data Editing - The CRU has placed data checks to identify out-of-range and missing entries, errors in dates (e.g., a follow-up done outside of the allotted time window.
• Updating -The CRU has enabled the eCRF to allow data entry personnel to correct data. The eCRF will maintain an audit trail of all data changes. Queries will be entered into the eCRF by the monitor or Quality Control personnel. The queries will be answered by the site, this will also be tracked.
• Reporting - The eCRF will describe and account for subjects accrued, entered, completed, etc.
• Statistical Analysis -The eCRF will have a mechanism to generate reports for statistical analysis.
• QC (Quality Control) Reports- will be sent to sites bi-weekly indicating missing/overdue data and outstanding queries. PI’s will also receive the QC reports to have oversight on their site’s data.
20.0 IMAGING TRANSFER All imaging data for the study is to be sent to the processing Core Lab located in Calgary, Alberta Canada. All stroke imaging completed in the first 48 hours should be transmitted to Calgary for assessment. Secure and efficient file transfer of imaging data will be performed using a web-based application called WebPAX. The WebPAX server is currently hosted in the U of C network and is administered by the IT personnel of The Calgary Image Processing and Analysis Centre (CIPAC, calgaryimageanalysis.ca). For access to WebPAX and account set-up contact Dr. Marina Salluzzi at [email protected]. Details are attached in Appendix 10. In the particular cases in which a site is unable to use WebPAX for the electronic transfer of imaging data an alternative means will be considered.
20.1 WEBPAX STUDY AND USER ACCOUNT SET-UP CIPAC personnel will be responsible for the set-up of a study node and the data workflow in the WebPAX application. CIPAC personnel will also contact the external sites to set-up their users account and perform training of the personnel in charge of uploading the imaging data to the server. Each authorized external user shall keep their own user account and login credentials confidential. Each user is responsible for all activity related to their account. All users shall ensure their account is only used for its intended purpose and that all activity is in compliance with the study standards. Immediate user account termination may be requested by the PI from whom the account creation originated (or appropriate substitute) or recommended by CIPAC IT personnel after an audit of user’s logs. 20.2 SYSTEM REQUIREMENTS As a web-based system, there are no significant technological requirements for external site users to use WebPAX. Each external site willing to electronically send imaging data to the core lab using WebPAX requires a computer with Chrome as Internet browser. If using Chrome is not possible updated version of internet explorer, safari, firefox and Java up-to-date will be needed. The personnel sending the images to the core lab does not require to have technical knowledge in imaging or IT, although minimal understanding of medical imaging and study specific protocol requirements will be needed. External site IT groups might be contacted if a site is unable to connect to WebPAX due to internal policies and security safeguards. In these cases, the external site personnel will engage their own IT group and if needed, CIPAC personnel will assist. 20.3 IMAGING DATA CURATION All imaging data should be sent to the core lab in a timely manner. The database manager will receive a daily e-mail notification of imaging data uploaded in the last 24 hours. It is the DB manager’s responsibility to perform curation over the received imaging data. Curation includes, but it is not restricted to, adding the case to an imaging data tracker, verifying the identifiers with the study database and applying quality control to the imaging data set. If at any point there is a need for clarification on the uploaded imaging data, the DB manager will contact the site directly. Instructions on what time to record in the database for each scan is outlined in appendix 10. If there are any questions with regards to this then contact the imaging manager and she can help you troubleshoot the times to record. 20.4 UPLOAD STEPS FOR IMAGING DATA. For access to WebPAX and account set-up contact Dr. Marina Salluzzi at [email protected]. 21.0 CONCOMITANT MEDICATIONS All medications administered to the subject will be recorded in the CRF from the time study drug is administered until the Day 5 visit. Concomitant medications will be recorded by general drug classifications. Previous medications will be recorded which will include all medications taken by the subject within 7 days of randomization, including medications given to the patient in Emergency prior to randomization. 22.0 ASSESSMENT TOOLS NIH Stroke Scale (NIHSS) and the Modified Rankin Scale
Certification: Any investigator or research coordinator completing the NIH Stroke Scale or the Modified Rankin Scale for the duration of the trial should be certified. A copy of all individual certificates will be filed in the Regulatory Documents Binder. For NIHSS certification or recertification you can access the training and exam online at: http://nihss-english.trainingcampus.net/uas/modules/trees/windex.aspx?resx=123 or http://learn.heart.org/ihtml/application/student/interface.heart2/nihss.html For Modified Rankin Scale Certification or recertification, you can access various training online sites for certification. Other local methods of training in the modified Rankin Scale will be accepted as well. This will be approved by the SI/Tempo-2 Coordinating Centre. See Appendix 3.0-6.0- for Samples of the NIHSS, the mRS, the EDQ5L and the IADL 23.0 REGULATORY DOCUMENTS 1. Regulatory Document Binder Maintenance
Each site has been provided with a pre-formatted electronic binder for all regulatory documents pertaining to the TEMPO-2 clinical trial. Regulatory Documents are stored in the TEMPO-2 Study Manager. Please note that this electronic regulatory document file contains confidential information. Only members of Health Canada, the TEMPO-2 Clinical Coordinating Center investigators and staff, and the clinical staff members authorized by the Principal Investigator at your site may have access to this information.
2. Documents Completed documents to be filed in the designated sections of the Regulatory Documents Binder include: 1) Study Site Signature Log and Delegation of Authority Log: This log is completed with the
printed name, role, effective date, initials, and original signature of all personnel to be involved in the conduct of this study. The DOA will describe the roles of participating study personnel for the study. This log must be continually updated and signed by the PI in a timely manner.
2) Staff Training Log: This log will reflect the training of study personnel on the protocol, NIHSS and mRS, good clinical practice training (GCP), informed consent training and study drug reconstitution and administration certification. Team members who are experienced in drug dispensing can be added to the delegation log for drug mixing only. In this case they just require training in drug reconstitution/ administration and do not require full GCP training.
3) Subject Identification Log: This log will record each subject’s name, medical record number, study identification number and study entry and completion dates. This is confidential information and must be maintained in a secure place at the study site.
4) Study Drug Accountability Log (if applicable): This log will indicate when the study drug was received at the site, dispensed to the subject and also returned. This log will account for all study drug.
5) Temperature Log (if applicable): This log will record the daily temperature of the storage of the study drug. It is reasonable that temperatures will not be recorded on the weekends or stat holidays.
6) Protocol / Amendment Signature Page(s): A photocopied version of the signed protocol page(s) should be filed in this section. Any revisions to the protocol will require a signed protocol amendment page. A copy should be forwarded to the TEMPO-2 Coordinating Center.
7) Protocol and Amendments: The original protocol and any subsequent amendments should be filed in this section.
8) Standard Operating Procedures (SOP): This document and any subsequent revisions should be filed in this section.
6) Curriculum Vitae/license: Copies of the curriculum vitae of the site’s principal and all sub-investigators should be filed here. Most current copies of medical/nursing licenses as appropriate should also be filed here.
7) Institutional Review Board / Ethics Committee Approval Letters: Documentation of the ERB approval of the protocol, protocol amendments, and informed consent should be filed in this section. Copies of all ERB documentation should be forwarded to the TEMPO-2 Central Coordinating Center via the TEMPO2 Study Manager.
8) IRB Correspondence: Documentation of request for ERB review of the protocol, protocol amendments, annual renewals and Informed Consent should be filed in this section. Correspondence and Reports to the ERB, and any protocol-specific correspondence between the Principal Investigator and the ERB should be included. Copies of all ERB documentation should be forwarded to the TEMPO-2 Central Coordinating Center.
9) Informed Consent: Blank copies of all versions the ERB-approved Informed Consent form(s) should be filed in this section. The site nurse coordinator should give the patient a copy of the Informed Consent. The original, signed Informed Consent form should be kept in the patient’s Case Report Form notebook. Copies can also be maintained in the patient’s medical chart.
10) Site Investigator Contact List: All versions of the Site Investigator Contact List must be filed in this section. Be sure to forward any revised or updated copies to the TEMPO-2 Central Coordinating Center.
11) General Correspondence: Any relevant study correspondence should be filed in this section. 12) Serious Adverse Event Reports: All communications containing information on serious and/or
unexpected events should be filed in this section. 13) Site Monitoring Visit Log: This log will be completed when the site is monitored or has been
visited by either Dr. Hill or Dr. Coutts or designated monitor. 14) Other: Signed Informed Consent forms for patients not enrolled. Also, any documents required
by each country’s regulatory body (i.e. REBA, QIU and CTSI. 24.0 SOP MAINTENANCE The SOP will be maintained and updated throughout this study. The SOP will be continuously reviewed by study staff to ensure that the operating procedures described are accurate. If any procedures are changed or modified, the SOP will be updated to reflect these changes and given to all participating sites for replacement.
APPENDICES AND STUDY FORMS APPENDIX 1.0
TEMPO-2 – LIST OF ABBREVIATIONS:
ACA Anterior Communicating Artery ACE Angiotensin converting enzyme AE Adverse Event AF Atrial Fibrillation ASPECTS Alberta Stroke Program Early CT scan ASA Acetylsalicylic Acid BI Barthel Index BP Blood Pressure CABG Coronary Artery Bypass Grafting CAD Coronary Artery Disease CASES Canadian Alteplase for Stroke Effectiveness Study CATCH CT And MRI in the Triage of TIA and minor Cerebrovascular events to identify High risk patients CBC Complete Blood Count CHD Coronary Heart Disease CHF Congestive Heart Failure CI Confidence Interval COPD Chronic Obstructive Pulmonary Disease CPR Cardiopulmonary resuscitation CRF Case Report Form CRU Clinical Research Unit CT Computed Tomography CTA CT Angiography CTA Clinical Trial Application CTP CT Perfusion CTSI Clinical Trial Site Information Form CV Curriculum Vitae CXR Chest X-ray DOA Delegation of Authority DBP Diastolic Blood Pressure DSMB Data Safety Monitoring Board DVT Deep Vein Thrombosis ECG Electrocardiogram eCRF Electronic Case Report Form ED Emergency Department ER Emergency Room FOIP Freedom of Information and Privacy Act FDA Food and Drug Administration FWA Federal wide Assurance GA General Anesthetic GCP Good Clinical Practice GI Gastrointestinal HIA Health Information Act HIPPA Health Insurance Portability and Accountability Act HTN Hypertension HR Heart Rate HSSS Historical Stroke Severity Score IA Intra-arterial ICF Informed Consent Form
ICH International Conference of Harmonization ICH Intracranial Hemorrhage ICU Intensive Care Unit IEC Internal Ethics Committee IND Investigational New Drug Application INR International Normalized Ratio IRB Institutional Review Board ISM Independent Safety Monitor IV Intravenous IVH Intraventricular Hemorrhage LDL Low Density Lipoprotein LMWH Low Molecular Weight Heparin LVH Left Ventricular Hypertrophy MCA Middle Cerebral Artery MI Myocardial Infarction MOP Manual of Procedures MRI Magnetic Resonance Imaging mRS Modified Rankin Scale N Number (typically refers to patients) NCCT Non Contrast CT NOL No Objection Letter NINDS National Institute of Neurological Disorders and Stroke NIH National Institute of Health NIHSS National Institute of Health Stroke Scale NS Normal Saline NSAIDs Non-steroidal Anti-inflammatory Drug MAP Mean Arterial Pressure O2 Oxygen PCA Posterior Communicating Artery PE Pulmonary Embolus PFO Patent Foramen Ovale PRN as Required PTT Partial Thromboplastin Time PVD Peripheral Vascular Disease PI Principal Investigator PIPEDA Personal Information Protection and Electronic Documents Act REB Research Ethics Board REBA Research Ethics Board Attestation RR Risk Reduction SAE Serious Adverse Event SAH Subarachnoid Hemorrhage SBP Systolic Blood Pressure SDH Subdural Hematoma SOP Standard Operating Procedure SWFI Sterile Water for Injection TIA Transient ischemic Attack TICI Thrombolysis in Cerebral Infarction tPA Tissue Plasminogen Activator tNK Tenecteplase VB Vertebral Basilar WBC White Blood Count
Research Title: TEMPO-2 – A randomized controlled trial of TNK-tPA versus standard of care for minor ischemic stroke
with proven occlusion
Sponsor Investigator: Dr. Shelagh Coutts
Principal Investigator: Dr. ____________
This consent form, a copy of which has been given to you, is only part of the process of informed consent. It should give you the basic idea of what the research is about and what your participation will involve. If you would like more detail about something mentioned here, or information not included here, you should feel free to ask. Please take the time to read this carefully and to understand any accompanying information.
Purpose
You are invited to participate in this research study because you have been diagnosed with a minor stroke caused by a blockage in a blood vessel of the brain that has occurred within the past 12 hours. Because most physicians believe that the outcome after minor stroke is mostly good and there is a potential risk of harm (bleeding) if clot-busting drugs are used, most treat conservatively with mild blood thinners such as aspirin. However, in patients with minor stroke with a blocked blood vessel, the risk of disability (a poor outcome) is much higher than commonly believed. The purpose of this research study is to evaluate effectiveness of the clot-busting drug, tenecteplase (TNK-tPA), compared to the standard treatment, which is an antiplatelet drug (e.g. Aspirin); for the treatment of minor stroke with an occluded artery within the brain occurring within 12 hours after symptom onset. Tenecteplase has not been approved for routine use in stroke patients by Health Canada. Tenecteplase could be helpful in the treatment for acute stroke due to blockage of an artery, even after including the risk of bleeding as noted above. You will be randomised (like tossing a coin) to receive either tenecteplase or standard of care (usually an antiplatelet drug) as part of the treatment you receive for your stroke. A total of 1274 subjects will take part in this study at approximately 60 hospitals throughout the world. Your participation in this study will last up to 90 days and includes one study visit to the Stroke Prevention Clinic, at day 90.
Procedures
As part of your usual care, you will usually have tests completed that are part of making the diagnosis and treating patients with stroke. These may include blood tests, vital signs, physical and neurological examination, review of your medical history, medication, neurological and social history, and brain imaging with CT or MRI etc. As part of this study we will have access to the results of these tests.
An extra scan, completed as part of the study, is a CT angiogram, (CTA) completed 4-8 hours post drug administration to see if the blocked artery has opened up again. The CTA scan involves the injection of an iodinated substance (contrast agent), which produces occasionally mild effects like itching, rash, nausea, fever and other signs of allergic reactions. Additionally, with an intravenous iodine injection, there might be a slight temporary burning sensation in your arm, a metallic taste in your mouth or whole body warmth. In patients with kidney disease the iodinated substance may cause damage to the kidney, which can be a serious condition. Your kidney function will be assessed by reviewing your baseline laboratory results, to ensure a follow-up CTA can be repeated. There also will be a single extra tube of blood taken to assess kidney function approximately 24 hours after treatment. Patients with a healthy kidney rarely encounter damage to the kidney after the injection.
Risks and Discomforts
Participation in the study may involve some risk. Because TNK-tPA dissolves blood clots, there is a risk of bleeding complications. Bleeding into the damaged brain can occur and can be serious in some patients since it can aggravate the symptoms of stroke (for example, your ability to walk, talk, and function independently) and it sometimes may cause permanent disability or death. Previous work suggests that in patients like you, this risk is low (1-2% of patients). There is also risk of serious internal bleeding which may require blood transfusion. In addition, there may be minor bleeding from gums or at sites where a puncture has been made to obtain blood samples or infuse medicine or fluid into a vein. A second known side effect of TNK-tPA treatment of stroke is swelling of the tongue and mouth (orolingual angioedema). This occurs rarely (1%) and is known to be associated with previous use of certain types of blood pressure medications. A standard treatment is available and no long-term side effects have been associated with this type of swelling.
You understand that during this study you will be observed very carefully. In response to any signs that indicate bleeding and at 24 hours after drug administration, a CT scan of your brain will be done to check for bleeding into the brain. Baseline and 24 hour CT scans are part of standard stroke patient care and involve exposure of only a small amount of radiation in addition to the usual x-rays studies done in stroke patients.
As with any drug, there is some chance of allergic reaction such as rash and you will be monitored and treated appropriately if any should develop. You will be monitored for all possible allergic responses. There also may be risks and discomforts, which are not yet known.
Possible Benefits
If you agree to participate in this study, there may or may not be a direct medical benefit to you. Your participation will provide information about the study treatment(s) and stroke that may benefit others by helping to provide better future treatments for patients with stroke. Your stroke may be improved during the study but there is no guarantee of that. The possible benefits to you from taking part in this study are close monitoring of your stroke, general health status, and any symptoms that you may experience during the study.
Alternate Treatments
You do not have to participate in this study to be treated for your stroke. If you do not participate in this study, you will receive the usual treatment for your stroke. This may include antiplatelet medications (such as aspirin), heparin, or other blood-thinning drugs. In addition, you can stop participation in the study at any time; your doctor may withdraw you from the study if they feel it is in your best interest. If you decide to withdraw from the study, the study staff will still have access to the data obtained up to the date when you withdrew from the study. Your participation in the study will not contain extra costs or financial compensations.
New Findings
You have been told that you will receive any new information during the course of the study concerning significant treatment findings that may affect your willingness to continue your participation.
Confidentiality
Records of participation in this research study will be kept confidential to the extent permitted by law. However, the TPD, HPFB, Ethics Committee (EC: a committee that reviews and approves research studies), and designated representatives of the Study's Clinical Coordinating Centre may inspect and copy records pertaining to this research. Although a patient code number will be used on all study documents that contain any medical information, it is possible that these records could contain information that personally identifies you. In the event of any report or publication from this study, your identity will not be disclosed. Results will be reported in a summarized manner in such a way that you cannot be identified.
I agree that my hospital chart and other records, including this consent form, may be looked at in confidence by authorized individuals from the study, by the University of Calgary, (the study sponsor) and other regulatory authorities (to check to ensure the study is carried out correctly). The signature page of the consent form will be encrypted and electronically transferred to the University of Calgary for review.
In the event that you are transferred from the hospital to a rehabilitation center, the rehabilitation center may send copies of your records and charts to the hospital where you were admitted. The rehabilitation center may also ask you to sign a form giving permission to send your records. If your records are duplicated and sent to the hospital, the doctors, nurses, and other health care professionals taking care of you, the sponsor of the study or their designee, the hospital EC, TPD, FDA and other regulatory agencies would also have access to these files. Participation in the study may involve research staff obtaining information (e.g. results of blood tests) from hospital electronic medical records, including Netcare.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as encouraged by Health Canada. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.
Compensation for Injury
In the event that you suffer injury as a result of participating in this research, no compensation or treatment will be
provided for you by the University of Calgary, Alberta Health Services, or the Researchers. You still have all your legal
rights. Nothing said here about treatment or compensation in any way alters your right to recover damages.
Consent SIGNATURES
Your signature on this form indicates that you have understood to your satisfaction the information regarding your participation in the research project and agree to participate as a subject. In no way does this waive your legal rights nor release the investigators or involved institutions from their legal and professional responsibilities. You are free to withdraw from the study at any time without jeopardizing your health care. If you have further questions concerning matters related to this research, please contact:
Dr. Philip Barber (403) 944-1594
If you have any questions concerning your rights as a possible participant in this research, or research in general, please contact the Chair of the Conjoint Health Research Ethics Board, University of Calgary at (403) 220-7990.
Participant’s Name Signature Date Time
Investigator/Delegate’s Name Signature Date Time
Witness’ Name Signature Date Time
The University of Calgary Conjoint Health Research Ethics Board has approved this research study. A signed copy of this consent form has been given to you to keep for your records and reference.
APPENDIX 3.0 Structured mRS - Taken from Bruno et al.
APPENDIX 4.0 NIHSS 1a Level of 0 = Keenly responsive
Consciousness: 1 = Not alert, but arousable by minor stimulation to obey, answer or respond 2 = Not alert, requires repeated stimulation to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped) 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid
1b LOC Questions: 0 = Answers both question correctly 1 = Answers one question 2 = Answers neither question
1c LOC Commands: 0 = Performs both tasks correctly 1 = Performs one task 2 = Performs neither task
2 Best Gaze: 0 = Normal 1 = Partial gaze palsy. This score is given when gaze is abnormal in one or both eyes, but where forced deviation or total gaze paresis is not present. 2 = Forced deviation, or total gaze paresis not overcome by the occulocephalic maneuver.
3 Visual: 0 = No visual loss 1 = Partial hemianopia 2 = Complete hemianopia 3 = Bilateral hemianopia (blind including cortical blindness)
4 Facial Palsy: 0 = Normal symmetrical movement 1 = Minor paralysis (flattened nasolabial fold, asymmetry of smiling) 2 = Partial paralysis (total or near total paralysis of lower face 3 = Complete paralysis of one or both sides (absence of facial movement in the upper and lower face)
5 Motor Arm: 0 = No drift, limb holds 90 (or 45) degrees for full 10 seconds 1 = Drift, limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not hit bed 2 = Some effort against gravity, limb cannot get to or maintain (if cued) 90 degrees 3 = No effort against gravity, limb falls 4 = No movement A= Amputation, joint fusion explain: ________________
5a Left: ____________ 5b Right _____________
6 Motor Leg: 0 = No drift, leg holds 30 degrees position for full 5 seconds 1 = Drift, leg falls by the end of the 5 second period but does not hit bed 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort against gravity 3 = No effort against gravity, leg falls to bed immediately 4 = No movement
6a Left: ____________ 6b Right _____________
7 Limb Ataxia: 0 = Absent If present circle each limb YES or NO 1 = Present in one limb Right Arm: YES NO Left Arm: YES NO 2 = Present in two limbs Right Leg: YES NO Left Leg: YES NO
8 Sensory: 0 = Normal; no sensory loss 1 = Mild to moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial pain with pinprick but pt. is aware 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm & leg
9 Best Language: 0 = No aphasia, normal 1 = Mild to mod aphasia: some obvious loss of fluency or facility of comprehension without significant limitation on ideas expressed or form of expression. 2 = Severe aphasia: all communication is through fragmentary expression; great need for inference, questioning , and guessing by the listener carries burden of communication 3 = Mute, global aphasia; no usable speech or auditory comprehension
10 Dysarthria: 0 = Normal 1 = Mild to mod: patient slurs at least some words and at worst, can be understood with some difficulty 2 = Severe: patient’s speech is so slurred as to be unintelligible in the absence of or out or a proportion to any dysphasia, or is mute/anarthric 9 = Intubated or other physical barrier explain: _________________________
11 Extinction and 0 = No abnormality Inattention (neglect) 1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to bilateral Simultaneous stimulation in one of the sensory modalities 2 = Profound hemi-inattention or hemi-inattention to more than one modality. Does not recognize own hand or orients to only one side of space
12a Distal Motor 0 = Normal Function: (Arm) A = At least some extension after 5 seconds, but not fully extended. Any movement of the fingers which is not command is not scored B = No voluntary extension after 5 seconds. Movements of the fingers at another time are not scored
12a L: ______________ 12b R ____________
APPENDIX 5.0 LAWTON BRODY
Instructions: Circle the scoring point for the statement that most closely corresponds to the patient's current functional ability for each task. The examiner should complete the scale based on information about the patient from the patient him-/herself, informants (such as the patient's family member or other caregiver), and recent records.
A. Ability to use telephone Score
1. Operates telephone on own initiative; 1 looks up and dials numbers, etc. 2. Dials a few well-known numbers 1 3. Answers telephone but does not dial 1 4. Does not use telephone at all 0
E. Laundry Score
1. Does personal laundry completely 1 2. Launders small items; rinses stockings, etc. 1 3. All laundry must be done by others 0
F. Mode of transportation
1. Travels independently on public 1 B. Shopping
1. Takes care of all shopping needs
1 transportation or drives own car 2. Arranges own travel via taxi, but does not
1
independently 2. Shops independently for small purchases
0
otherwise use public transportation 3. Travels on public transportation when
1
3. Needs to be accompanied on any shopping trip
0
assisted or accompanied by another 4. Travel limited to taxi or automobile with
0
4. Completely unable to shop C. Food preparation
0 assistance of another 5. Does not travel at all
0
1. Plans, prepares, and serves adequate meals independently
1 G. Responsibility for own medications
1. Is responsible for taking medication in 1
2. Prepares adequate meals if supplied with ingredients 3. Heats and serves prepared meals, or prepares meals but does not maintain adequate diet 4. Needs to have meals prepared and served
0
0
0
correct dosages at correct time 2. Takes responsibility if medication is prepared in advance in separate dosages 3. Is not capable of dispensing own medication H. Ability to handle finances
0
0
1. Manages financial matters independently 1 D. Housekeeping
1. Maintains house alone or with occasional
1 (budgets, writes checks, pays rent and bills, goes to bank), collects and keeps track of
assistance (e.g., "heavy work domestic help") 2. Performs light daily tasks such as
1
income 2. Manages day-to-day purchases, but needs
1
dishwashing, bed making 3. Performs light daily tasks but cannot
1
help with banking, major purchases, etc. 3. Incapable of handling money
0
maintain acceptable level of cleanliness
4. Needs help with all home maintenance tasks 1 5. Does not participate in any housekeeping 0 tasks
(Lawton & Brody, 1969)
Scoring: The patient receives a score of 1 for each item labeled A – H if his or her competence is rated at some minimal level or higher. Add the total points circled for A – H. The total score may range from 0 – 8. A lower score indicates a higher level of dependence.
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APPENDIX 6.0- EQ-5D- EUROQOL QUESTIONNAIRE
By placing a check-mark in one box in each group below, please indicate which
statements best describe your own state of health today.
Mobility
I have no problems in walking about 0 I have some problems in walking about 0 I am confined to bed 0
Self-Care
I have no problems with self-care 0 I have some problems washing or dressing myself 0 I am unable to wash or dress myself 0
Usual Activities (e.g. work, study, housework, family or leisure activities)
I have no problems with performing my usual activities 0 I have some problems with performing my usual activities 0 I am unable to perform my usual activities 0
Pain/Discomfort
I have no pain or discomfort 0 I have moderate pain or discomfort 0 I have extreme pain or discomfort 0
Anxiety/Depression
I am not anxious or depressed 0 I am moderately anxious or depressed 0 I am extremely anxious or depressed 0
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To help people say how good or bad their state of health
is, we have drawn a scale (rather like a thermometer) on
which the best state you can imagine is marked 100 and
the worst state you can imagine is marked 0.
We would like you to indicate on this scale how good
or bad your own health is today, in your opinion. Please
do this by drawing a line from the box below to
whichever point on the scale indicates how good or bad
your state of health is today.
Your own
state of health
today
100
9 0
8 0
7 0
6 0
5 0
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APPENDIX 7.0- CRF COMPLETION GUIDELINES
Electronic CRF Completion Guidelines
➢ Please refer to these iDatafax guidelines for assistance and clarification on completing the forms in the database. If you have any questions regarding completion of any section of the CRF, please feel free to call or email the TEMPO-2 Coordinating Centre: [email protected].
➢ The timeline for information to be entered into the eCRF will be 7 days from the visit being performed.
➢ In most cases the paper CRF requires a signature and the investigators name is then typed into the database.
➢ PI (Principal Investigator) sign off is required for 1) Inclusion/Exclusion Criteria 2) End of Study 3)
SAE’s (Serious Adverse Events) acknowledging data completion and trial oversight.
Missing Data
➢ Enter one of the following if data are not available:
Not Known = UNK, Not Applicable = NA, Not Done = ND
Note: For protocol mandated assessments that are missing enter NK/NA/ND or the appropriate
abbreviation.
➢ In case an entire page is empty (e.g. blank Adverse Event page, prior conmeds, etc.) please tick the “NO” box at the top of the page and the page will be complete.
➢ If a page cannot be completed (e.g. assessment not performed- NIHSS as Day 90) mark the page as “LOST”. Go to header “Page”, then go down to “Mark page as Lost” and enter the reason why the page/assessment was not completed. No data or queries can be entered on this page in order to mark page as “LOST”.
➢ If there is a missing value or unknown, go to the bottom right of the eCRF page- click on the … (3 dots) and select “Missing Value”. You can also reset the field if missing value was chosen, but you later find the field information (No Code-reset).
➢ Please save the page as “Incomplete” if data is missing or you need to return back to the page to
update with more information at a later time.
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When time should be recorded, use the 24-hour clock (3.45AM = 03:45; Noon = 12:00; 4.15PM =
16:15; Midnight = 24:00). A new calendar day starts at 00:01 and ends at 24:00. No value of 00:00 will
be accepted.
Enter the date using the following formats: DDMMMYYYY (e.g., 22FEB1963)
List of month abbreviations:
January JAN February FEB March MAR
April APR May MAY June JUN
July JUL August AUG September SEP
October OCT November NOV December DEC
Patient ID
The participant ID is a 5 digit number consisting of a 2-digit site number followed by a 3-digit sequential participant number (e.g. 01-002; 01 = site number, 002 = patient code). The PID is assigned by site personnel at the time of signing the informed consent form. The PID MUST be used consistently throughout the study and must only be assigned for one participant.
Date at the Top of the CRF Page:
The date the assessment was completed helps to confirm that the pages completed were done in that time period. Record the MMM/DD/YYYY format in the header.
Times and Dates
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What to do at Screening: (-7days to randomization)
➢ Informed Consent- either Surrogate or Patient
➢ Review all Inclusion and Exclusion Criteria
➢ Demographic Data
➢ Medical History
➢ Creatinine (local lab)
➢ Pregnancy test (local lab)
➢ NIHSS
➢ Modified Rankin Scale
➢ Prior Medication
Help Icon
Click on the “HELP” box at the top right-hand corner of each CRF to toggle to the corresponding instruction page. Hit the enter key to toggle back.
Randomization Plate 1
This plate will be reviewed and managed by the TEMPO-2 Coordinating Centre. Any discrepancies in information will be verified by the Source and with Site Personnel. Queries will be posted by Data Management and answered by the CRU. No need to answer queries on this page. View Only Status for all Sites.
If you note an error on the Randomization Plate, please email [email protected]
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Inclusion Criteria Plate 002 Record `No` or Yes` for each of the inclusion criterion on the protocol inclusion checklist in the CRF.
If NO to any of the inclusion criteria, DO NOT enroll the patient. If discovered after enrollment, update the CRF (change response for “Yes” to “No”) and provide an explanation in the Reason for Data value box in order to document the protocol violation.
A Protocol Deviation pop-up box will come on the page as a reminder to complete a Protocol Violation (Major) Form (Plate 028)
Criteria must be YES to all boxes #1-#7.
Inclusion #3: NIHSS may be 0 for patient to be enrolled. NIHSS entered from 0-5.
Inclusion #4: an intracranial occlusion must be present on CTA OR a focal perfusion abnormality identified by CTP
Inclusion #5: Please refer to Plate 011 for mRS instructions and baseline value.
Inclusion #6: There is a 10-minute allowance allotted for the time from CT scan to treatment. This accounts for the differences in watches, clocks in ER and times noted. Any treatment time over 100 minutes will be considered a major protocol deviation. Only change response to ‘NO’ if the patient was treated beyond 100 minutes.
Inclusion #7: Informed consent must be obtained prior to any study related procedures and randomization.
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Exclusion Criteria Plate 003 If YES to any of the exclusion criteria, DO NOT enroll the patient. If discovered after enrollment, update the CRF (change response for “NO” to “Yes”) and provide an explanation in the Reason for Data value box in order to document the protocol violation.
A Protocol Deviation pop-up box will come on the page as a reminder to complete a Protocol Violation (Major) Form (Plate 028)
Exclusion #5: Conduct a pregnancy test (serum or urine) and provide the date and results for females of childbearing potential who are not surgically sterile. If results are positive, do not enroll.
Exclusion #6: Any patient at the time of randomization, you already have a plan to treat with endovascular therapy should not be enrolled. If the patient deteriorates after randomization, this question should still be answered “no” and a Protocol Deviation Form be completed. (Plate 027)
Exclusion #8: All of these exclusion criteria are relative contraindications for thrombolytic treatment. You may enroll patients who have fulfill one or more of these criteria at the discretion of the treating/ enrolling investigator. If one of the exclusions are checked “Yes”, please ensure that the Investigator writes a note in the patients’ chart stating the reasoning and rationale for enrollment. Record the exclusion under Medical History. (Plate 5). Read carefully the wording of the exclusion, for example, a patient who had a CABG 10 weeks ago, that the treating physician does not consider a contraindication to thrombolysis. In this case, please check “No”.
All local labs should be measured according to local practice. Local lab results DO NOT need to be
reviewed prior to patient enrollment.
Eligibility Criteria eSignature-Plate 51
The PI (Principal Investigator) of the trial for each site must sign off on this page after each patient enrollment. PI must confirm that all Inclusion and no Exclusion Criteria were met. Only the PI has access to sign off on this page, even if a Co-Investigator enrolled the patient.
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Demographics Plate 004
Sex: refers to a person’s biological status and is categorized as male or female.
Race: Select all that apply:
• Caucasian: A person having origins in any of the original peoples of Europe, the Middle East or North Africa
• First Nations: An organized aboriginal group or community, or a person having origins in any of the original peoples and who maintain tribal affiliation or community attachment. (e.g. Canadian Inuit, Australian Aborigines)
• Pacific Islander: A person having origins in any of the original peoples of Hawaii, Guam, Samoa, or the other Pacific Islands.
• Asian: A person having origins in any of the original people of the Far East, Southeast Asia, or the Indian subcontinent, including for example: Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand and Vietnam.
• Black: A person having origins in any of the black racial groups of Africa
• Other: Race cannot be determined, was not reported by patient or local regulations do not allow reporting. Or any other ethnicity that does not fit in the above sections.
Ethnicity: Base the answers on how the patient thinks of his/her own ethnicity.
Select the correct category:
• 01- Not Hispanic or Latino: A person NOT meeting the definition of Hispanic or Latino
• 02- Hispanic or Latino: A person of Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture of origin, regardless of race.
Onset of Stroke Symptoms: Please record the time that the patient was either last seen/known
well or time of witnessed stroke onset.
Date and Time of Emergency Arrival at the Investigational Hospital Enter the date and time the patient was admitted to the investigational site. If the patient had been
seen at another hospital and then transferred to the investigational site, please use the time the
patient presented to the investigational hospital. Informed Consent Obtained: Patient must
provide signed informed consent form before any study procedures are done. Please record the date
of signature.
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Past Medical and Surgical History Plate 005 ➢ Please record all relevant present and past diseases and diagnosis.
➢ Only record relevant observations from the baseline physical examination not belonging to the current stroke. Do not record stroke symptoms.
➢ ICH: Intracerebral Hemorrhage
➢ CHF: Congestive Heart Failure
➢ Record any Exclusion #8 (plate 002: a-j)
➢ Record if Carotid Stenosis was diagnosed on CTA at baseline
➢ Record if patient is post-menopausal or tubal ligation if pregnancy test was not performed in
women.
Neurological Exam- Randomization Plate 006
➢ Please record the patients worst deficits i.e. based on either their description or your
examination of them, up to the time of randomization.
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Labs/Bloodwork Baseline Plate 007 ➢ If any baseline labs are out of range or abnormal, and the Investigator feels they are clinically
significant, please record on the Medical History page. The database will flag out of range values. If blood work is taken at 2 different times e.g. due to hemolysis, then the date and time of the first lab draw should be recorded.
➢ Platelets: If platelet count is below 100,000 per cubic millimeter and results are reviewed after patient enrollment, please record this in the medical history. This will not be considered a protocol deviation, as lab results are not required to be reviewed prior to enrollment.
➢ INR: if >1.7, this must be reported as a Protocol Deviation.
➢ Creatinine: Please check the Baseline Creatinine to ensure the patient may have a follow-up CTA at 4-8 hours post randomization.
➢ Pregnancy: Conduct a pregnancy test (serum or urine) and provide the date and results for
females of childbearing potential. If results are positive, do not enroll.
ECG Plate 008
➢ Please note the date and time of ECG is preferred be prior to Study Drug Administration, but can be performed out to 6 hours post randomization.
➢ Any Clinically Significant results (e.g. Atrial Fibrillation) on the baseline ECG must be
recorded in the Medical History Section (if done prior to randomization).
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NIHSS Plates 9 and 10
➢ The baseline NIHSS must be performed at baseline prior to randomization.
➢ A change in 4 points or greater from the baseline NIHSS will be recorded as Neurological Worsening and recorded as a SAE. If the treating Investigator feels that the worsening in the NIHSS is due to a concomitant illness, such as a UTI-urinary tract infection, sedation, etc., then please document this in the patient’s chart as well as a “Reason for Data Value” with an explanation. This does not need to be reported if worsening is not to due neurological reasons.
➢ The database will flag any increase in the NIHSS in all follow-up NIHSS assessments out to Day 5.
➢ Day 5 or Discharge: Please perform at Day 5 or sooner if patient is discharged. If the patient is discharged at 24 hours, then the NIHSS will be entered on the Day5/Discharge form with the same NIHSS value and date. If patient is discharged at 48 hour or Day 3, please enter this date and assessment under Day 5 OR Discharge. The patient does not have to be contacted at Day 5 if they were discharged earlier than Day 5.
➢
➢ A blinded evaluator must perform the day 90 NIHSS assessments. A blinded assessor is defined as someone who has not been involved in the patients’ care in the first 48 hours, also blinded to the treatment allocation and location of intracranial occlusion/imaging.
Modified Rankin Scale Plate 011
➢ For Baseline: please record the pre-stroke functioning status of the patient.
➢ A score greater than 2 at Baseline will result in the database flagging the response. This will then be recorded as a protocol violation - Major.
➢ For the follow up visits: please interview and ask appropriate questions to ensure the correct score. Please follow the questions asked in the form in detail to the patient to determine the score. If patient is not back to working due to symptoms then they are scored a 2.
➢ The day 90 assessments must be done by a blinded assessor. A blinded assessor is defined as
someone who has not been involved in the patients’ care in the first 48 hours also blinded to
the treatment allocation and location of intracranial occlusion/imaging.
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Baseline CT/CTA Site Assessment Plate 012
➢ Please record the ASPECTS score total.
➢ Please note that both “left” and ‘right” or “NA” can be selected. NA should only be selected if the occlusion site is in the brainstem. In this scenario, the ASPECTS should be scored as 10.
➢ Select the most proximal relevant lesion or select the most relevant vascular territory if
perfusion used for enrollment –only one occlusion location is permitted.
Treatment Assignment Plate 013
➢ Enter the date and time the bolus of tenecteplase was started.
➢ Start time of Study drug will be the Start of the Bolus.
➢ Blood Pressure Pre-Study Drug: Please record the blood pressure within 10 minutes of administering study drug or control treatments. This is true for both tenecteplase and control groups. The treating Investigator may choose not to treat the BP Pre-Study Drug if the patient is randomized to the Control Group. This is not a Protocol Deviation, as it is the judgement of the treating physician not to treat the BP at that time.
➢ For Control group, please record the date and time the patient received the first drug after randomization. If the patient was already given a treatment prior to randomization, e.g. Aspirin, and no other medications are being given, then record this date and time. Also, record the medication on the prior medications form – plate 21. The Control group must be treated within 90 (+10 minutes) from the first slice of the CT.
➢ Record the LOT number and expiry date of the tNK. The expiry date is the last day of the month, for example, Aug2020 will be entered as 31Aug2020. No LOT number information is required for the Control group.
➢ Please have the Investigator administering the tNK sign the CRF page.
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Consent Upload-Plate 54
Please upload the Signature Page of the Informed Consent that the patient or Surrogate signed prior to randomization in the TEMPO-2 Study Manager Site. https://tempo2.cru.ucalgary.ca/ DO NOT upload into iDatafax. No identifiable information can be entered into iDatafax.
24 Hrs Lab/Bloodwork Plate 014
➢ Time windows start from the time of Randomization for the 4-8 hour and 24-hour follow-ups.
➢ If the Creatinine is out of range or abnormal, and the Investigator feels this is clinically significant, please record on the Adverse Event Page (Plate 23)
➢ Weight: Record the value and tick the appropriate unit tick box (kg or lbs).
➢ Actual Weight: This weight will be collected anytime from baseline out to Day 5.
Patient Location Form Plate 015
➢ This form is either filled out at day 5 or on the day of discharge if discharge is sooner than 5
days.
➢ The patient will be considered discharged if they go to a rehabilitation unit, even if the rehabilitation unit is at the treating hospital. This would be considered a rehabilitation facility.
➢ Please complete this form at the Day 90 visit, to capture the discharge date, if patient wasn’t previously discharged at Day 5.
➢ At Day 90, “Date of discharge” is considered to be the date of discharge from acute care for the stroke admission.
➢ At Day 90, if the patient was readmitted to hospital between the original acute discharge and
Day 90, please tick “other” and enter a comment, as well as report a SAE (plate 24) for
➢ Please complete this form to capture any imaging that was performed from baseline through 48 hours.
➢ Please record the “first slice” of each imaging modality that was used.
➢ It is requested that all imaging be transmitted to the TEMPO-2 Core Lab within 7 days of patient enrolment.
➢ If the 4-8 hour CTA was not performed due to CTP being used at baseline or renal insufficiency or Investigator choice, please comment in “Reason for Data Value” and enter explanation why CTA was not performed.
➢ A 4-8 hour CTA must be performed in both treatments arms.
➢ Imaging performed outside of the 24-hour window will be entered as “Other”.
➢ Any questions in regards to imaging please email Marina Salluzzi- the TEMPO2 Core Lab Manager at [email protected].
EQ5D (Quality of Life Assessment) Plate 017,018
➢ Please complete this form at the Day 90 follow-up visit. Usually the patient can complete this himself or herself. For part B record the score on scale in the box. This assessment can be performed over the telephone if the patient is unable to return for the Day 90 assessment.
IADL- Instrumental Activities of Daily Living Plate 019,020 ➢ Please complete this form at the Day 90 follow-up visit. Select the best answer for each
question. This assessment can be performed over the telephone if the patient is unable to
return for the Day 90 assessment.
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End of Study/Completion Plate 277
➢ Please complete this form at any time point the patient has completed the study. If the patient died or withdrew from the study prior to the Day 90 assessment, please record the last date of contact with the patient, or the date of death.
➢ The PI (Principal Investigator) sign off will be completed when the patient has completed participation in the trial. The PI sign off acknowledges the patient has completed the trial and is aware of any new findings, e.g. a new SAE reported at Day 90. The PI sign off does not indicate that all data is complete and accurate- queries may still be posted after PI sign off. The Sponsor prefers PI sign off as soon as possible after the patient has completed the trial which indicates PI oversight of the patient’s data and not wait for data to be monitored and finalized.
End of Study eSignature Plate 52 ➢ The PI (Principal Investigator) sign off will be completed when the patient has completed
participation in the trial. The PI sign off acknowledges the patient has completed the trial and is aware of any new findings, e.g. a new SAE reported at Day 90. The PI sign off does not indicate that all data is complete and accurate- queries may still be posted after PI sign off. The Sponsor prefers PI sign off as soon as possible after the patient has completed the trial which indicates PI oversight of the patient’s data and not wait for data to be monitored and finalized.
➢ This role is assigned only to the Site PI and no other Coinvestigators for sign off.
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Prior Medications Plate 021
➢ Please record any medications the patient has taken within 7 days prior to randomization.
➢ Please record the GENERIC drug name.
➢ Please record any medications given in the ambulance or in Emergency including any antihypertensives to treat the baseline blood pressure prior to randomization. This includes if the patient was given an anti-platelet in ER prior to randomization.
➢ If the concomitant medication is being administered due to an ongoing disease that started prior to study drug start, record the corresponding diagnosis on the ‘Past Medical and Surgical History’ page.
➢ Only record the start date of the medication, if medication was newly started given in the 7 days prior to randomization.
➢ If “Continuing” is checked, please re-enter this medication on the Conmed page. Often a
prior medication taken by the patient may be stopped the day of admission and restarted
the following day. Please enter this medication on the Conmed page with the date it was
restarted.
Concomitant Medications Plate 022
➢ If patient remains on a Conmed at Day 5, please check “continuing”.
➢ Conmeds may be requested by the TEMPO-2 Coordinating Centre for reporting a SAE event.
➢ If the concomitant medication has been initiated for an AE, complete a corresponding ‘Adverse Event’ page.
➢ Do Not Record: CT Contrast Media, IV Solutions, Oxygen, Multi-Vitamin or Mineral Supplements.
➢ Please record the GENERIC drug name.
➢ Treatment Start Date: Should be from the time of randomization until and including Day 5. If the patient was taking the medication at home and had no interruption, then record the prior med box and re-enter on the Conmed page if continuing after admission.
➢ Treatment End Date: If patient remains on a Conmed at Day 5, please check “continuing”.
➢ Concomitant medications include any medications given to the control group. Tenecteplase is not considered a concomitant med.
➢ At Day 90, please review the Conmeds and check any “continuing” medications.
If stopped prior to Day 90, please update the stop date.
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Adverse Events Plate 023
➢ Only record AEs (i.e. occurring after randomization), including SAEs, on this CRF page.
➢ AEs are recorded from the time of randomization until Day 5. If an AE is still ‘ongoing’ at Day 5, please leave as ongoing/unresolved. Only SAE’s are reported from Day 5 through Day 90.
➢ At Day 90, please review any “ongoing/unresolved AE’s” and update the status. Please answer the question at the bottom of the form if “ongoing”. If AE has resolved, please enter the date of resolution. The AE pages will show as “red/incomplete” if the AE is ‘ongoing’ until it is completed and checked at Day 90.
➢ Record the diagnosis or syndrome for all AEs. For example, if the patient had shortness of breath due to congestive heart failure, please record ‘Congestive heart failure’ as the adverse event. Do not record ‘shortness of breath’. As a last resort, if there is no clear diagnosis, provide the most relevant or the main sign/symptom of the AE.
➢ Use precise medical terms (e.g. ‘brain edema’ instead of ‘edema’) and avoid the use of abbreviations (‘myocardial infarction ’instead of ‘MI’).
➢ Onset Date and Time: Record the start date of the AE. Time must be entered. Please use time of imaging, or time stated by nursing staff, pt. or choose an arbitrary time. A time must be entered and cannot be left blank.
➢ Outcome Date and Time: Record the date, when the AE resolved with/without sequelae. An end time must be entered- use an arbitrary time if unknown or per patient’s recall.
➢ Severity: AE’s will be categorized as:
• Mild: Awareness of a sign or symptom which is easily tolerated
e. g.: headache, rash, edema.
• Moderate: Discomfort enough to cause interference with usual activity
e. g.: Urinary Tract Infection, hypokalemia
• Severe: incapacitating or causes inability to work or undertake usual activities. E.g.: Pneumonia, intracerebral hemorrhage
➢ If the reported AE caused death or contributed to death, enter the date of death as ‘Resolution Date’. This date should correspond to the date of death entered in ‘Study Completion’. An AE that causes death is by definition a SAE. See below for reporting instructions.
➢ If an AE was not resolved at the time of death but did not contribute to the fatal outcome, leave the resolution date field empty.
➢ If an AE was not resolved at Day 5, leave the resolution date field as “continues”, please
follow-up at the Day 90 visit for most recent status and update form.
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Serious Adverse Events Plate 24, 25
➢ Please complete this form within 24 hours of notification of the SAE event. Enter the SAE event on the Adverse Event page and mark as “Serious”. A prompt will pop up to remind you to complete the SAE page. All SAEs thus will have both an AE entry and then the additional entry on the SAE page to collect the relevant additional information required for SAE reporting.
➢ Outcome Events are also reported as a SAE. Please report TIA’s with DWI imaging on MR- even if the patient was not admitted but seen in clinic or follow-up.
➢ All SAE’s will be collected throughout the duration of the trial, until the patient has been seen at Day 90 or end of study has been declared.
➢ Please complete all fields on the SAE pages (1 and 2), including start and stop times of SAE. Page must be saved as “FINAL”.
➢ Please enter as much detail into the narrative as relevant, starting at the onset of symptoms until the SAE occurrence. Please include the following items in the SAE narrative:
▪ Age of patient at time of randomization
▪ Sex
▪ Date and onset of qualifying event with presenting symptoms to ED ▪ Location of the occlusion for randomization
▪ Time of study drug treatment in relation to the stroke onset
▪ Description of the SAE including diagnosis
▪ Medications or other steps were taken to treat SAE
▪ List any relevant tests, imaging, laboratory data, history, including preexisting medical conditions
▪ Investigator’s determination of the relationship of SAE event to the Study Drug ▪ Any follow-up or planned follow-up with the patient
➢ Entry into the database will trigger notification of the TEMPO-2 Coordinating Centre that a SAE
has been entered into the system. The Coordinating Centre may contact sites for more information about the SAE event.
➢ Report any SAE to your local Research Ethics Board according to local ethics board rules. The eCRF database will allow the SAE narrative page to be copied out of the database into another document used to notify your REB.
➢ Please forward a copy of the notification to your REB to the TEMPO-2 Coordinating Centre, as well as the Acknowledgement letter from the REB.
➢ For sites where there is co-ordinated central notification process for all sites in given province/state or country (e.g. in the province of Quebec), reporting of SAEs to ethics boards will be co-ordinated by one site in that jurisdiction.
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Privileged and Confidential
Protocol Deviation Plate 027 ➢ Please record any Protocol Deviations on this page. Record the action taken, if needed,
retraining, etc.
➢ As per your local Institutions REB reporting, please report any protocol deviations. The TEMPO-2 Coordinating Centre does not require reporting to the REB for minor Protocol Deviations.
➢ Please complete a separate form for each Protocol Deviation and Action taken.
➢ Pop-ups will come up on page suggesting if a Protocol Deviation should be completed as a reminder.
➢ Any questions regarding reporting Protocol Deviations, please email:[email protected]
Protocol Violations – Major Plate 028
➢ Please record any Protocol Violations-Major on this page. This includes any Inclusion or Exclusion Criteria that was not met or any other options on Plate 028 that would be defined as a Major Protocol Violation. Exclusion #8 does not need to reported as a Major Protocol Violation if the discretion of the treating Investigator chose to enrol the patient. Please make a note in the CRF or “reason for data value”.
➢ Record the action taken and if needed, retraining, etc.
➢ As per your local Institutions REB reporting, please report any Protocol Violations- Major. The TEMPO-2 Coordinating Centre requires reporting to the REB for all Major Protocol Violations.
➢ Please complete a separate form for each Major Protocol Violation and Action taken.
APPENDIX 9.0- STUDY MANAGER INSTRUCTIONS Randomization Once informed consent has been obtained then open the randomization website. http://tempo2.cru.ucalgary.ca
Use your email/ password that we will request around the time of your site initiation visit. Logins are individual rather than site specific. Once you are logged in you will reach the randomization page.
You need to click on the questions “is the patient eligible to randomize?” and “was informed consent obtained” to be able to randomize. This is a good opportunity to check that your patient meets all the inclusion and exclusion criteria. The information you require to randomize is:
• Year of birth - type this as free text),
• Month of birth - chose from the drop down list),
• Sex - chose from the drop down list),
• Your site - chose from the drop down list),
• NIHSS - (0-5, chose from the drop down list), This is the NIHSS completed just before randomization.
• Date and time of onset – click on the date. Once you have clicked on the date, time options will pop up. If you require a number that does not end in a 0 or a 5 then you can manually edit the number that you click on.
After you have entered all this information you then click on randomize patient. The next page will summarize the information you have entered in and give you an opportunity to check this. If no changes are required then click on randomize the patient. You then are taken to a page which tells you what arm the patient has been randomized to: (experimental (tenecteplase) versus control). If the patient is randomized to the Tenecteplase (TNK) arm, then the print out will tell you that the patient has been randomized to 0.25mg/ Kg, and it will calculate the dose that you need to give the patient. Where possible print this page out and put this in the patients CRF. If it is not feasible at the time then this can be done later. To do this you would login to the website and click on patient list. Chose the correct patient and click on it. The randomization form can be printed off from here too.
