2. Agenda 8:00-8:10Welcome and review of INTERACT1 (Tom Robinson) 8:10-8:30 INTERACT2: protocol, website, worldwide update (Emma Heeley) 8:30-8:40 INTERACT2 in the UK (Tom Robinson) 8:40-8:50 Discussion

3. INTERACT pilot results Tom Robinson

4.  Aimed to assess the safety and efficiency of intensive BP lowering in acute ICH  In 404 patients, results showed that early intensive BP lowering was:  Safe  Feasible  Produced modest reduction in haematoma growth at 24 hours - appeared to limit ongoing bleeding by about 20-30% (~2ml, or about ½ teaspoon) in intracerebral haemorrhage (Lancet Neurology 2008; 7:391-399) Lancet Neurology 2008 May;7(5):391-399

5. INTERACT1: pilot study Acute spontaneous ICH onset < 6 hours SBP ≥150 and ≤220 mmHg No definite indications or contraindications to treatment Able to be actively managed Provide informed consent Repeat CT scans 24 + 72 hrs Vital signs and BP over 7 days 28 day and 3 month follow-up Intensive BP lowering Target systolic BP 140 mmHg within 1 hour and for 24+ hrs Standard BP management AHA Guideline-based (treatment if systolic BP >180 mmHg) R Standard best practice stroke unit care

6. INTERACT1- Adjusted mean absolute and relative increase in haematoma volume Absolute increase in haematoma volume GuidelineIntensiveGuidelineIntensive 6 2 -2 30 10 -5 0 4 20 0 P=0.13 P=0.06 Δ-10%Δ-1.7ml ml % Relative increase in haematoma volume

7. Consistency of P >0.05 for heterogeneity in subgroups 36% (-19 to 65%) 36% (-24 to 67%) 57% (-3 to 82%) 24% (-28 to 55%) 15% (-73 to 50%) 47% (6 to 70%) 38% (-24 to 69%) 30% (-25 to 61%) 37% (-3 to 62%) 31% (-93 to 76%) 24% (-45 to 61%) 45% (-2 to 70%) Age <65 years 65+ years Time to randomization <3 hours 3+ hours Baseline systolic BP  mean >mean Baseline diastolic BP  mean >mean History of hypertension Yes No Baseline NIHSS  median >median 13 (15%) 23 (23%) 13 (15%) 17 (23%) 6 (12%) 14 (27%) 20 (16%) 26 (22%) 12 (13%) 14 (15%) 14 (17%) 26 (32%) 12 (12%) 16 (20%) 14 (19%) 24 (27%) 21(16%) 32 (25%) 5 (13%) 8 (18%) 13(15%) 18 (20%) 13 (15%) 22 (28%) Favours standard Favours intensive Relative risk Reduction (95% CI) Number (%) of patients with event Intensive (n=201) Standard (n=203) 0.1 1.0 2.1 Rate ratio

8. INTERACT1 – Adverse events to 90 days (%)

9. INTERACT1 – Clinical outcomes at 90 days

10. INTERACT2 Emma Heeley

11. New design : simpler, easier, quicker  Option of second CT scans  600 patients to investigate haematoma growth  Reduced in-hospital assessments but assessment of ICU stay and use of renal dialysis  Option of telephone based outcome assessments at 28 and 90 days

12. INTERACT2: main study Acute spontaneous ICH onset < 6 hours SBP ≥150 and ≤220 mmHg No definite indications or contraindications to treatment Able to be actively managed Provide informed consent Repeat CT scans 24 hrs in selected patients Vital signs and BP over 7 days 28 day and 3 month follow-up Intensive BP lowering Target systolic BP 140 mmHg within 1 hour and for 24+ hrs Conservative BP management AHA Guideline-based (treatment if systolic BP >180 mmHg) R Standard best practice stroke unit care

13. Inclusion Criteria  Age 18 years or more  Acute spontaneous ICH (history and CT)  At least 2 Systolic BP 150-220 mmHg, recorded 2 or more minutes apart  Able to be randomly assigned BP lowering therapy within 6 hours of stroke onset  Able to receive active (‘intensive’) care in a monitored facility

14. Exclusion Criteria  Known definite contraindication to intensive BP lowering  Known definite indication to intensive BP lowering  ICH due to secondary to structural abnormality  Ischemic stroke in last 30 days  High likelihood of death within 24 hours (GCS 3-5)

15. Exclusion Criteria cont’d  Known advanced dementia or significant pre-stroke disability  Concomitant medical illness  Planned early surgical intervention  Participation in other trial  Unlikely to adhere to treatment or follow-up

16. INTERACT2 BP Management  Evaluation of a management policy and NOT of a single agent  Pragmatic approach to treatment  Agents readily available in hospitals  Agents approved for clinical use  Lower study costs  Inclusion of BP lowering management protocols for key available agents

17. Schedule of Assessments

18. INTERACT 2 Website  Internet-based randomisation and data collection system  24-hour password protected website using encryption software  An internet connection from the study centre (eg ED or stroke unit)

19. 2 Website Addresses 1.TEST https://test.thegeorgeinstitute.org/interact2 2.LIVE https://studies.thegeorgeinstitute.org/interact2 Each site has: - Separate user names and passwords - Distinguished by different colours. TEST website is purple/yellow LIVE website is purple/white

20. Electronic Signature  Authorised study staff will electronically sign all computerised forms  All changes will have a complete audit trail  Data can be accessed and edited at any time  Query generation and resolution performed instantly  An Authorised Signature Form is required to obtain a username & password

21. Accessing INTERACT Website 1.Go to the website address 2.Type in User Name & Password in the Login box 3.Click on the Login button

22. Prior to Randomisation Confirm eligibility Complete hard copy of Form A To be eligible for INTERACT2: All inclusion criteria questions must be answered “YES” All exclusion criteria questions must be answered as “NO” Randomisation is performed on the website

23. Test Randomisation TEST website: https://test.thegeorgeinstitute.org /interact2

24. Successful Randomisation Notified of :  Unique patient study number Randomised to either:  intensive BP lowering treatment or  control current guideline-based management of BP Patients will be stratified according to: time since stroke onset (0-4 vs. 4-6 hours), site and country of recruitment  Important to write these details in patient medical records and print a copy for your file

25. Screen shots of randomisation

26. 8 Electronic CRFs  Form A (Randomisation Form)  Form B (Baseline & Medical History)  Form C (Day 1 Assessment)  Form D (Day 7 Assessment)  Form E (BP Assessments)  Form F (Day 28 Assessment)  Form G (Day 90 Assessment)  Form X (SAE or Outcome)

27. Electronic Case Report Forms  Review of INTERACT Database  Test database  https://test.thegeorgeinstitute.org/interact2 https://test.thegeorgeinstitute.org/interact2  Live database  https://studies.thegeorgeinstitute.org/interact2 https://studies.thegeorgeinstitute.org/interact

28. Form B Baseline & Medical History

29. Screening log  Simplified  Only for 1 month of each year

30. Any questions regarding the website?

31. INTERACT2 – Current Network

32. Recruitment Number of patients randomised

33. Recruitment RegionRandomised Patients* Australia43 China1178 India22 Pakistan3 Chile2 Austria43 Belgium2 France101 Germany54 Italy14 Portugal6 Spain10 *as of 26/Nov/2010

34. Comparison of recruitment in INTERACT2 and other ICH trials (analysis 01/Nov/2010) NameDate Duration (months) CentresSponsorPatients Recruitme nt rate per month Recruitme nt rate per centre INTERACT2 2008 25 83 NHMRC 140856.317 STICH 1995- 2003 156107 MRC 10336.69.6 FAST 2005- 2007 40122 NovoNordisk 841216.8 CHANT 2003- 2005 29133 AstraZeneca 60720.94.6 INTERACT1 2005- 2007 18 44 NHMRC 40422.49.2 NovoSeven 2002- 2004 20 73 NovoNordisk 399205.5

35. Comparison baseline characteristics INTERACT1 and 2 INTERACT1 (n= 404) INTERACT2 ( n= 1223) Median time from ICH onset to hospital presentation (hours) 1h30 (50min – 2h30) 1h20 † (45min – 2h10) Median time form ICH onset to randomisation (hours) 3h40 (2h53 – 4h50) 3h40 (2h48 – 4h35) Mean age (years)*62 (12)63 (12) Females35%37% Country of residence Asia97%87%‡ Other3%13% Medical history Hypertension74%73% Previous ICH11%8% Ischaemic stroke11% Acute coronary event3%2% Diabetes8% Drug use Anti-hypertensive therapy43%38% Anti-platelet therapy8%6% Warfarin anticoagulation1%2% Clinical features at randomisation Systolic BP (mm Hg)*181 (18)180 (17) Diastolic BP (mmHg)*103 (14)104 (16) Heart rate (beats per min)*79 (14)77 (13) Median NIHSS score9 (5-15)11 (5-15) Median GCS score14 (13-14)14 (12-15) GCS score≤ 98%6% INTERACT1 (n= 404) INTERACT2 ( n= 1223) Median time from ICH onset to hospital presentation (hours) 1h30 (50min – 2h30) 1h20 † (45min – 2h10) Median time form ICH onset to randomisation (hours) 3h40 (2h53 – 4h50) 3h40 (2h48 – 4h35) Mean age (years)*62 (12)63 (12) Females35%37% Country of residence Asia97%87%‡ Other3%13% Medical history Hypertension74%73% Previous ICH11%8% Ischaemic stroke11% Acute coronary event3%2% Diabetes8% Drug use Anti-hypertensive therapy43%38% Anti-platelet therapy8%6% Warfarin anticoagulation1%2% Clinical features at randomisation Systolic BP (mm Hg)*181 (18)180 (17) Diastolic BP (mmHg)*103 (14)104 (16) Heart rate (beats per min)*79 (14)77 (13) Median NIHSS score9 (5-15)11 (5-15) Median GCS score14 (13-14)14 (12-15) GCS score≤ 98%6% INTERACT1 (n= 404) INTERACT2 ( n= 1223) Median time from ICH onset to hospital presentation (hours) 1h30 (50min – 2h30) 1h20 † (45min – 2h10) Median time form ICH onset to randomisation (hours) 3h40 (2h53 – 4h50) 3h40 (2h48 – 4h35) Mean age (years)*62 (12)63 (12) Females35%37% Country of residence Asia97%87%‡ Other3%13% ‡ ‡ p <0.001

36. INTERACT2 - Mean systolic BP time trends Δ13 mmHg at 1 hour; Δ10 mmHg at 24 hours Mean SBP Worldwide Analysis completed on 01/Nov/2010

37. Comparison Between Regions: mean systolic BP differences at 1 hour Mean SBP per Region Mean SBP Region Analysis completed on 01/Nov/2010

38. INTERACT2 important reminders: Form E  Day 1 is the day of randomisation regardless of the time the patient is randomised. Therefore, if a patient was randomised at 11:00 PM on Day 1, Day 2 blood pressure data entries may overlap with blood pressure data entries within the first 24 hours of randomisation.  In addition, if a patient has died prior to Day 7, some BP fields might be left empty

39. INTERACT2 important reminders: Outcome assessment (days 28 and 90)  Day 28 and day 90 outcome assessments are to be undertaken by an investigator who was not involved in the clinical management of the patient, and blind to the randomised treatment allocation.  These assessments can be conducted at 28±3 days and 90±7 days, by telephone interview or at a face-to-face outpatient consultation.

40. Progress over the past year  Data Safety Monitoring Board (DSMB) interim analysis (~1300 patients with 90 day outcomes) on 26/Aug/2010. Recommended to continue the trial with no protocol changes  Further network expansion into South America, Northern Europe and UK  Half-way recruitment (1,400 patients) met on 29/Oct/2010

41. INTERACT2 in the UK Tom Robinson

42. Update on progress  Ethics  University of Leicester UK sponsor  Monitor/CRA based at University of Leicester

43. Update on progress  Ethics  University of Leicester UK sponsor  Monitor/CRA based at University of Leicester

44. Ethics  Nottingham REC 1 12 Oct 2010  Conditional Approval (subject to Chair action), Reply 01 Nov 2010  Short Version PIS/ RIS  Clarification of 2 CT Head scans (1 routine clinical, 1 study specific)  Context of 3% IS risk with BP reduction  GP IS  Results Lay Summary (SRN website)

45. Sponsorship  Main Sponsor ICC, Sydney  UK Sponsor UoL  Insurance Document available  Division of responsibility between Main and UK sponsor to be agreed

46. Monitor  Based within UoL  JD being finalised  Advert/ Interview/ In Post

47. UK  Up to 15 centres  Over 100 patients  Recruitment period ………….  FPI ……………..

48. INTERACT2 Discussion Thank you very much! Tom Robinson: tgr2@leicester.ac.uktgr2@leicester.ac.uk International Coordinating Centre: interact@george.org.au interact@george.org.au Emma Heeley: eheeley@george.org.aueheeley@george.org.au Michelle Leroux: mleroux@george.org.aumleroux@george.org.au