Centralized Imaging Services H. LUNDBECK A/S Stroke - Desmoteplase DIAS-4 Investigators Meeting, Chicago, July, 2011 Presented by Thomas Truelsen, Lundbeck

DIAS-4 Study Imaging summary 1/2 IndicationStroke Total number patients 400 randomized and completed patients (BL and 12-24h) (Estimated 800 screened patients (BL only)) Imaging time point - Baseline hrs - Unscheduled (from BL to D90) Imaging Modality MRI: DWI + MRA + T2* + T2 FLAIR (Perfusion Imaging (PI) as optional sequence, only for sites confirmed by Lundbeck to provide their PI source data) CT: NCT + CTA

DIAS-4 Study Imaging summary 2/2 Image collection On-going Image Collection and Quality Control Central Reading and Assessments Eligibility reading: inclusion/exclusion criteria at BL Safety reading: Presence of ICH Hemorrhage or Ischemic Oedema at 12-24hrs and Unscheduled Quantitative reading: Assessment of Infarction Volume at BL and 12-24hrs Vessel status reading: Vessel status at BL and recanalization sub-study at 12-24hrs

DIAS-4 Study Imaging Worflow Start up phase Running phase of the study of the study Site Imaging Evaluation Study supplies Image Collection & Initial Check Image Quality Control Query Management Central Reading Organization Data transfer to sponsor Site Phone Training

Site Imaging Evaluation (1/6): Purpose For Synarc: - Verify the ability of each site to acquire images according to the requirements described in the Imaging Manual and the MR & CT Procedure Manual - Verify the readibility of the images in Synarc Imaging software (DICOM format) For the site: - Sites are encouraged to record the DIAS-4 study specific parameters in the device(s) (according to settings pre-defined in the Imaging Manual). - These parameters are not mandatory any more, however, in order to standardize the imaging procedure study sites are highly recommended to stick to them.

Site Imaging Evaluation (2/6): Workflow Investigator Site 3 Qualification Notification LUNDBECKLUNDBECK SYNARCSYNARC 4 Imaging package shipment 1 Initial site selection questionnaire 2 Filled in questionnaires new imaging survey

Site Imaging Evaluation (3/6): Before study start each study site should fill in an imaging survey with data on potential CT or MRI scanners to be used in this trial – E.g. brand, software, availability of DICOM standard, availability of DICOM saving, etc.. Phantom scans no longer needed Each survey can be filled in with information for 3 CT and 3 MRI scanners Already qualified scanners do not need to be entered in the survey The forms should be sent via to Jamal Smyej After evaluation the study site will receive an notification from the imaging lab Synarc

Site Imaging Evaluation (4/6): Site supplies Evaluation survey: – Provided to the site once site has been selected for the trial Complete supply package: – Provided to the sites once evaluation completed – to perform exam acquisitions all along the study: Imaging Binder containing Imaging Manual and Procedure Manual triplicate Transmittal Forms and pre-labelled CD-ROMs Courier shipping material (UPS) One acknowledgement of receipt to be faxed back to Synarc upon package receipt

Site Imaging Evaluation (5/6): MR&CT Imaging Procedure Manual Document which summarizes imaging protocol and data handling All personnel involved in the imaging part of the trial (Neuroradiologist, Technologist, Study Coordinator) need to read and fully understand the Imaging Manual And to sign Page i of the Imaging Procedure Manual Please fax a copy of this completed page to Synarc San Francisco Keep original in the procedure manual

Site Imaging Evaluation (6/6): Remote Site Phone Training Purpose: Logistical Training provided by Synarc to site (by phone). It is organized once complete supply package has been received and has to be followed by the MRI and/or CT technologist and the study site Coordinator. Content: – Presentation of the study material and documents – Image acquisition details – Image and exam identification – Package preparation and shipment (FedEx) – Data Clarification Form For information: Additionally to the Synarc phone training, one web-based training will be coordinated and organized by Lundbeck to provide information regarding eligibility criteria.

Image acquisition and collection (1/6) : Image flow Store images on the CD-ROM. Fill in the patient/visit information on the CD-ROM Place the Transmittal Form (original) and the labeled CD-ROM in the padded envelope Images to be shipped to SYNARC via courier Images should be sent to SYNARC within 2 days of acquisition Fill in the Transmittal Form, Fax it to SYNARC San Francisco Keep yellow and pink copies at site. A copy of all images must be kept at site

Image acquisition and collection (2/6) electronical data transfer A new option has been agreed on with Synarc to replace shipment of physical films by an FTP transfer This change should not be forced on to sites as mandatory – but rather implemented where the sites think this could be an advantage A short feasibility questionnaire need to be sent to the sites to check for compatibility The CRAs will be asked to send the FQ to the sites and feedback the results of the discussions to Lundbeck and Synarc

Image acquisition and collection (3/6) : Expected exams/sequences MRICT Post- Processed Images Central Assessment Purpose Baseline (BL) Scout DWI T2* T2 FLAIR MRA PI (optional) Scout NCT CTA All Post- processed Images to be sent to Synarc (Trace/ADC for DWI, MIP/3D Reconstruction for MRA and CTA, Maps for optional PI) Eligibility reading - check of the exclusion and inclusion criteria: - Exclude hemorrhage - Include occlusion in MCA M1, MCA M2, ACA or PCA Quantitative Reading: - Assess the Initial Infarct Volume Vessel Status Reading (TIMI): - Confirm vessel status (presence of occlusion) Perfusion: to be discussed between Lundbeck and Synarc Hrs (12-24h) Scout DWI T2* T2 FLAIR MRA (substudy) PI (optional) Scout NCT CTA (substudy) Safety Reading: - Assess the presence of hemorrhage or ischemic oedema Quantitative Reading: - Assess the Final Infarct Volume Vessel Status Reading (TIMI) (substudy): - Check vessel recanalization Unscheduled (UNS) All Unscheduled Scans performed within the study from BL to D90 to be sent to Synarc Safety Reading: - Assess the presence of hemorrhage or ischemic oedema

Image acquisition and collection (4/6) : Image Labeling Main information needed for images identification: – Study patient number – Date of Birth – Acquisition date – Visit code Please be careful to anonymize/de-identify the images for legal reasons Make sure to enter the cerebral hemisphere side affected by the acute stroke in the image. DICOM FIELD:To be entered at the time of acquisition: PATIENT NAME Make sure that subject name (or patient address, social security number, phone number) is NOT entered or if entered, make sure to anonymize/de-identify it before making the CD-Rom copy. PATIENT I.DEnter Patient Screening number as reported on the CRF (S+4digits e.g :S0001) PATIENT DATE OF BIRTH Enter Patients date of birth as reported on the CRF PATIENT COMMENTS Enter Site ID as reported on the CRF (2 letters+3 digits e.g :IN001) PATIENT GENDER Enter Patient gender as reported on the CRF. ADDITIONNAL PATIENT HISTORY Cerebral Hemisphere side affected by the acute stroke: Enter Right for right hemisphere or Left for left hemisphere STUDY DESCRIPTION Visit code: Enter the visit code corresponding to the visit: BL (Baseline), 12-24h (12-24 Hours), UNS (Unscheduled) Same information has to be present on transmittal form and within the images.

Image acquisition and collection (5/6) : Transmittal Forms

Image acquisition and collection (6/6): Transmittal Forms Filling the Transmittal Forms Contains the description of the images sent (to be filled-in according to the GCP guidelines): Patient and visit information Image acquisition (series number burnt on the CD-ROM) Air waybill number Name and signature of Technologist Form to be faxed to Synarc before shipment of the entire data package Good Clinical Practices – Use black or blue ink – Write clearly and legibly – Correct mistakes properly (strike through error, put initials and date next to correction) Do NOT use correction fluid – Fill out the forms properly – Use the labels provided for CDs – Include proper signatures – Maintain subject and clinical protocol confidentiality – Contact SYNARC for any questions/problems 02-JAN-2006 JUN Error-MMS 03JUN06

Image Quality Control (1/2) Presence and readability of all documents (first check) – Presence of all the documents per visit (transmittal form and CD) – Verification of the readability of the documents (images format) Anonymity – If images not anonymised yet: anonymisation done by SYNARC Patient identity / Date of Acquisition of the scan – Proper labeling of the images in accordance with the transmittal form information (patient and visit information) Complete scan – Compliance to the imaging protocol and presence of sequences required by the protocol Imaging parameters – Presence of the information required for the quantitative evaluation (slice thickness, …)

Image Quality Control (2/2): Query Management Query Management: In case of missing information, missing image, discrepancy between the information … SYNARC will send a Data Clarification Form by to the site The site will have to send back the Data Clarification Form filled by fax and if necessary with other documents

Central Reading (1/3): Eligibility Reading SYNARC Investigators center IP Networ k Inclusion /exclusion criteria Feedback to sponsor Io Workstation QC, Anonymization Randomization Inclusion /exclusion criteria Inclusion /exclusion criteria Imaging Committee Workstations

Central Reading (2/3): Safety and vessel status Reading Safety Reading: – Central Reading pannel to assess the presence of Hemorrhage and/or Ischemic Oedema Vessel status and recanalization Reading: – Central Reading pannel to assess the vessel status from baseline and 12-24h follow-up images

Central Reading (3/3): Quantitative Assessment - Central Reading pannel to assess infarct volume - Validation or correction of the ROIs by the central Reader of the Imaging Committee - Automatic calculation of the volume using the imaging lab reading workstation (using information from DICOM header (slice thickness, slice position…) Volume of the lesion ROIs delineated on the images

Staying in touch Clemence Blondeau Project Manager at Synarc Jamal Smyej Imaging specialist at Lundbcek Synarc Inc Gateway Boulevard Bldg 5, 3rd Floor Newark, CA USA

Thank you! Any questions?