Imaging Overview

DIAS-4

Randomised, double-blind, parallel-group, placebo-controlled phase III study to evaluate the efficacy and safety

of desmoteplase in acute ischemic stroke

Investigational product: Desmoteplase (INN)

Although desmoteplase was not better than placebo in the overall DIAS-2 patient population, exploring the subgroup of patients with proximal cerebral arterial occlusion or high-grade stenosis

at baseline (TIMI 0 to 1) revealed a treatment effect of desmoteplase vs. placebo of 17% (90 µg/kg) and 10% (125 µg/kg) respectively.

Purpose of Imaging in DIAS-3 and DIAS-4

Results from Phase III trialDIAS II

50,0 51,9 49,0

0

10

20

30

40

50

60

Res

po

nse

Rat

e (%

)

Placebo n=58

Desmoteplase90 g/kg n=52

Desmoteplase125 g/kg n=49

Response defined as achievingall 3 of the following:• ≥ 8 point NIHSS improvement or 0-1 AND • mRS score 0-2 AND• Barthel Index 75-100

MRI Results DIAS II

19%n=76

13% effect size

Inclusion Criteria

27. The subject shows signs of extensive early infarction on MRI or CT in any affected area that is, an infarcted core involving >1/3 of MCA territory or > 1/2 of the ACA or PCA territories

28. The subject has imaging evidence of ICH or SAH (regardless of age of the bleeding); Arterio-Venous malformation; cerebral aneurysm; or cerebral neoplasm (incidental meningioma and microbleeds per se are not exclusion criteria. An incidental intracranial aneurism that is small (< 5 mm), not thrombosed, and not visibly bleeding is not an exclusion criterion)

29. The subject has a parenchymal hyperintensity on FLAIR, T2*, or EPI-T2 images, or marked hypodensity on CT, indicative of subacute infarction, or enhancement with morphologic features suggesting the lesion is more than 9 hours old*.

*“Bright, not subtle, hyperintensity on T2-FLAIR indicating any subacute infarction. Patients presenting with subtle or slight hyperintensity on FLAIR in the region of DWI lesion can be enrolled according to the protocol. Patient presenting with patterns of less acute infarction within the territory of the obstructed artery, e.g. with cortical hemorrhagic transformation or contrast enhancement, having a clearly demarcated infarction on FLAIR, must not be enrolled”

Imaging exclusion criteria (1/2)

Imaging Exclusion Criteria (2/2)

30. The subject has an internal carotid artery occlusion on the side of the stroke lesion

31. The subject has a contraindication to the imaging technique (that is, ferromagnetic objects for MRI, contraindications to contrast agent, etc. Refer to the Imaging Manual for contraindications to imaging technique)

32. The subject has any intracranial pathology that would interfere with the assessment of the chosen imaging technique for screening

Selection of Imaging Modality

• The sites will identify either MRI or CT or CT & MRI as their diagnostic imaging modality

• Each participating site showed evidence of sufficient experience in acute imaging of stroke patients with their chosen modality(ies) and qualified as study centres.

• For perfusion assessment, MRI sites need to show evidence of sufficient experience in acute ‘penumbral’ MRI-PI/DWI imaging of stroke patients. Perfusion CT (PCT) is not planned for the DIAS-3 trial.

General Sequence (1/2)

• Baseline examination – identify infarction – exclude extended infarction or ICH.– Occlusion/severe stenosis of ACA, MCA (proximal branches), or PCA

The infarct size assessment at baseline will be performed based on native CT or DWI (qualitatively).

• follow up examination 12 -24 h– hemorrhagic infarction, – parenchymal hematoma – extend of infarctionImaged with non-contrast CT or DWI (and T2*, FLAIR)

• The infarct size assessment at 12 – 24hwill be performed by the imaging modality that was used at baseline (native CT or DWI).

• If a patient clinically deteriorates, and an unscheduled CT scan is performed prior to 12 h after drug administration, the 12 - 24 h examination may be omitted only if the scan shows a haemorrhage.

• The vessel status of the patients participating in the recanalisation sub-study will be assessed at 12 - 24 hours after study medication administration. The interested sites will be asked to repeat MRA or CTA, using the baseline modality, at 12 – 24h.

• Independent of any imaging finding, scan time and date, all unscheduled imaging examinations of the brain performed during the individual participation in the study (from baseline to day 90) should be sent to the imaging lab (e.g. in case of patient deterioration).

General Sequence (2/2)

Timing issues (1/2)

• The study protocol states: “The subject should receive IMP within 60 minutes after completion of diagnostic imaging screening”

• The following proposal has been agreed upon in order to ease patients’ enrollement:

– a. We will keep the 60 minutes as it is currently stated in the selection criterion and urge the sites to do their best to observe that time period to treat patients.

– b. In the case of sites only performing CT (no MRI available): if the patient cannot be treated within 60 minutes a repetition of NCT is required until 120 minutes. After 2 hours, new imaging with NCT and CTA is required otherwise the patient may not be included.

– c. MRI sites should repeat all the study related sequences if the patient is not able to receive study medication within 60 minutes after completion of baseline diagnostic imaging.

Stroke MRI

• MRA • DWI• T2*• FLAIR

– Perfusion only in selected sites

Sequence

Baseline scout DWI MRAT2

FLAIR T2* (PI)1 -

12 - 24 hours scout DWI (MRA)T2

FLAIR T2* (PI) or CT

Stroke CT

• Nativ CT• CTA

– No Perfusion studies

Timing Type of examination

Baseline Non-contrast CTCTA

•12-24 hoursNon-contrast CTCTA is to be repeated only for sites participating in the recanalisation substudy

TIMI grading in CTA & MRA

.

TIMI 0

Follow-up

Initial

TIMI 1

TIMI 2

TIMI 3

• Implement Dias imaging protocol

• Invite everyone to screen for DSPA treatment

• Invite your colleagues to participate to the reader training

• Randomized trials are the only way to get any new drug into the field

To Dos

Any questions?