1 US Investigator Meeting DIAS-4, Chicago, July 2011 DIAS-4-USA Study Protocol.

1 US Investigator Meeting DIAS-4, Chicago, July 2011

DIAS-4-USAStudy Protocol

US Investigator Meeting DIAS-4, Chicago, July 2011

Purpose of presentation

2

Present and discuss the DIAS-4-USA Study protocol


Agenda

Overview of protocolSelection CriteriaExcl. & concomitant medicationStudy Committees

Discussion & questions as we go along


Study overview - DIAS-3/4

Confirm efficacy of desmoteplase 90ug/kg vs. placebo

Two-arm, phase III, pivotal study

Neuroimaging to identify responders treated 3-9h post stroke


Study title

A randomised, double-blind, parallel-group placebo-controlled phase lll study to evaluate the efficacy and safety of desmoteplase in subjects with acute ischemic stroke

DIAS-3/4; Desmoteplase In Acute ischemic Stroke


Outline of study design

12-24h

Placebo

90 ug/kg DSPA


Study objectives

Primary objective- To evaluate the efficacy of desmoteplase 90 μg/kg versus

placebo in terms of favourable outcome at Day 90 in subjects with acute ischemic stroke

Secondary/other objectives (not exhaustive)- Favourable outcome at different time points- Favourable outcome in subgroups of patients with

- “Small” core lesion (less than 25 cc)

- Recanalisation (12-24 hrs)

- Different mismatch volumes (optional)


More secondary objectives

Safety and tolerability- Mortality- Symptomatic Intracranial Haemorrhage- Immunogenicity of desmoteplase

Pharmacoeconomics- Evaluate Quality of Life & Utilisation of Resources

Population pharmacokinetics- Two blood samples at 0.5-9 hours post-treatment


Key differences to DIAS-2

DIAS-2

N=186 (1:1:1)Dose-ranging (PBO, 90

& 125 ug/kg)Patient selected based

on penumbra imagingPrimary endpoint:

mRS/NIHSS/BI

DIAS-3/4

N=400 (1:1)Single dose (PBO &

90ug/kg)Patients selected based

on angiographyPrimary endpoint:

(mRS 2)


Primary efficacy endpoint

Good clinical outcome at Day 90 defined as:

mRS score of 0-2

mRS

0 = No symptoms

1 = No sign. disabil., + symptoms

2 = Slight disability

3 = Moderate disability

4 = Moderately severe disability

5 = Severe disability

6 = Death

mRS

0 = No symptoms

1 = No sign. disabil., + symptoms

2 = Slight disability

3 = Moderate disability

4 = Moderately severe disability

5 = Severe disability

6 = Death


Effect size on primary endpoint

N = 400 patientsPost-hoc analysis showed 29% difference (mRS 2)Power of 80%, alfa of 5%Study is powered to detect 13% difference on mRS

(mRS 2)


Study population overview

Patients with an occlusion or high-grade stenosis on MCA, ACA or PCA

Patients eligible for treatment within 3-9 hoursScore of 4-24 on NIHSS at baseline

- Very mild and very severe strokes are excluded

Age 18-85Exclusion of patients that:

- Have an increased risk of haemorrhage

- Are not expected to benefit from thrombolysis


Inclusion criteria (#1-3)

1. Clinical diagnosis of acute ischemic stroke

2. Informed consent/HIPAA authorisation has been obtained according to a procedure approved by the ethics committee responsible for approval of the study at this site.

3. Male or female between 18 and 85 years of age inclusive


Inclusion criteria (#4-6)

4. Treatment of the subject can be initiated within 3 – 9 hours after the onset of stroke symptoms. If the actual time of

onset of stroke is unclear, then the onset will be considered the time that the subject was last known to be well. All measures are to be taken so treatment with alteplase within 3 hours of symptom onset is not delayed in subjects who qualified for receiving alteplase

5. The subject has a score of 4 - 24 inclusive on the NIHSS with clinical signs of hemispheric infarction

(for example, hemiparesis)

6. The subject must receive IMP within 60 minutes after completion of diagnostic imaging screening. The time stamp on the last imaging sequence is the reference for calculating the time elapsing.


Inclusion criteria (#7)

7. The subject shows occlusion or high-grade stenosis as assessed by on MRA or CTA in proximal cerebral arteries that corresponds to the acute clinical deficit. Eligible vessels are the middle cerebral artery MCA M1, MCA M2, anterior cerebral artery (ACA) or posterior cerebral artery (PCA)


Exclusion criteria (#1,4,5)

1. The subject has a pre-stroke mRS score of >1, indicating previous disability

4. The subject has a terminal illness with a life-expectancy of less than 6 months

5. In the opinion of the investigator, the subject has any condition that could impose hazards to the subject, if study therapy is initiated, or affect the participation of the subject in the study (for example, subject with metastatic cancer or with severe microangiopathy such as hemolytic uremic syndrome or thrombotic thrombocytopenic purpura)


Exclusion criteria (#6-8)

6. Consciousness level >2 on question 1a of NIHSS

7. The subject has a history or clinical presentation of ICH, subarachnoid hemorrhage (SAH), arterio-venous malformation, aneurysm, or cerebral neoplasm. Subjects with incidental small intracranial aneurysm can be considered for the study if the aneurysm is < 5 mm, not thrombosed, and not visibly bleeding

8. The subject has symptomatic acute vertebral or basilar artery occlusion



13. The subject has a baseline platelet count < 100,000/mm³

14. The subject has a baseline haematocrit of < 0.25

15. The subject has a baseline blood glucose < 50 mg/dl or > 200 mg/dl (< 3 mmol/l or > 11 mmol/l). Subjects with blood glucose value between 200-300 mg/dl can be considered for the study only if the blood glucose value decreases to < 200 mg/dl after antidiabetic treatment and before administration of IMP

16. The subject has uncontrolled hypertension defined as a blood pressure > 185 mmHg systolic or >110 mmHg diastolic on at least 2 separate occasions at least 10 minutes apart, or requiring aggressive treatment to reduce the blood pressure within the limits. The definition of aggressive treatment is left to the discretion of the investigator



17. The subject has a hereditary or acquired hemorrhagic diathesis

18. The subject has had a gastrointestinal or urinary bleeding within the past 21 day

19. The subject has had an arterial puncture at a non- compressible site within the past 7 days

20. The subject has had another stroke or a serious head injury in the past 6 weeks

21. The subject has had major surgery within the past 14 days


Exclusion criteria (#22-23, 25-26)

22. The subject has had seizure at the onset of stroke

23. The subject has had an acute myocardial infarction (AMI) within the past 3 weeks

25. The subject is a pregnant woman (positive serum βHCG pregnancy test, positive urine pregnancy test or clinically evident pregnancy)

26. The subject is, in the opinion of the investigator, unlikely to comply with the clinical study protocol or is unsuitable for

any other reason


Compare with alteplase contraindications

Active internal bleeding Severe uncontrolled hypertension Recent intracranial or intraspinal surgery or trauma (within 3 months) Intracranial neoplasm, arteriovenous malformation, or aneurysm Known bleeding diathesis History of cerebrovascular accident Evidence of intracranial hemorrhage Suspicion of subarachnoid hemorrhage History of intracranial hemorrhage Seizure at the onset of stroke Platelet count less than 100,000/mm Administration of heparin with 48 hours preceding the onset of stroke and

have an elevated activated partial thromboplastin time at presentation (ischemic stoke)


Excluded medication, Excl. Criteria (#2-3)

2. The subject has previously been exposed to desmoteplase

3. The subject has participated in any investigational study in the past 30 days


Excluded medication, Excl. criteria (#9-11)

9. The subject is on oral anticoagulants and has a prolonged prothrombin time (INR > 1.6)

10. The subject has been treated with heparin in the past 48 hours and has a prolonged partial thromboplastin time exceeding the upper limit of the local laboratory normal range. Preventive low doses of LMWH (for example, for deep vein thrombosis (DVT) prophylaxis) do not disqualify the subject from the study

11. The subject has been treated with glycoprotein IIb - IIIa inhibitors within the past 72 hours. Use of single agent oral platelet inhibitors (e.g. clopidogrel 75 mg or low-dose aspirin < 325 mg) or the combination of low-dose-aspirin (e.g. 50 mg) and dipyridamole (e.g. 400 mg) prior to study entry is permitted


Excluded medication, Excl. criteria (#12, 24)

12. The subject has been treated with factor Xa inhibitors in the past 72 hours

24. The subject has been treated with a thrombolytic agent within the past 72 hours


Concomitant Medication

The following concomitant medications

are not allowed during the study:Any other thrombolytic agent within the first 72 hours

after IMP administrationAny antiplatelet agent within the first 24 hours after IMP

administrationAny anticoagulant within the first 24 hours after IMP

administrationAny endovascular/mechanical treatment of stroke within

72 hours after IMP administration


Reiterate imaging

Baseline- Confirm diagnosis and ensure occlusion/high-grade stenosis - exclude ICH & other pathologies- Centres may perform imaging by either MRI or CT- MR centres may obtain Perfusion Image (not selection!)

12-24 hour imaging- To monitor for cerebral bleedings (symptomatic) by CT or MRI

and before the initiation of anti-thrombotic therapy- To assess recanalisation and infarct size


Reiterate imaging (cont.)

Imaging selection criteria will be discussed in the imaging session

Unscheduled scans needed- In case of neurological deterioration- In case of worsening of NIHSS >4 (between baseline

and Day7)- After Day 7: if NIHSS worsens >4 compared to Day

7 score and there is no reason for the worsening


Steering Committee

Greg Albers (co-chair), USRüdiger von Kummer (co-chair), GermanyMarkku Kaste, FinlandAntoni Davalos, SpainAshfaq Shuaib, Canada Gary A Ford, UKHugues Chabriat, FranceJames Grotta, USLee Schwamm, USK C Chang, Taiwan


Data Monitoring Committee

Kennedy Lees (chair), UKLaurance Wechsler, USMichael Eliasziw, Canada


Imaging and Adjudication Committees

Imaging CommitteeJochen Fiebach (Chair), GermanySalva Pedraza, SpainKarl-Olov Lövblad, SwitzerlandJavier Romero, US

Adjudication CommitteeRüdiger von Kummer, GermanyAnthony Furlan, USHoward Rowley, US


Summary

Post-hoc analyses of DIAS-2 and previous studies have identified a scientifically/pathophysiologically sound target population for DIAS-3/4

Selection of patients based on presence of occlusion/high-grade stenosis

Still compatible with ’penumbra concept’ (and mismatch data will be obtained)


Summary (cont.)

Objective of DIAS-3/4 is to confirm efficacy and safety of Desmoteplase 90ug/kg

Two pivotal, global studies planned to enrol a total of 800 patients with acute ischemic stroke

Overall purpose to fulfil a huge medical need in acute ischemic stroke in the 3-9 hr time-window


Questions?

1 US Investigator Meeting DIAS-4, Chicago, July 2011 DIAS-4-USA Study Protocol.

Documents

us investigator meeting

study overview dias

mrsnihssbi dias

acute ischemic stroke

death slide

usa study protocol slide

mrs mrs

severe disability