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1. A collaboration led by

2. INTERACT2:Protocol

3. INTERACT2: New design features • Reduced number of in-hospital assessments but includes and assessment of ICU stay and use of renal dialysis • Repeat 24 hr CT scan to be collected only in 600 patients (300 Chinese and 300 non-Chinese) • Option of telephone-based outcome assessments at 28 and 90 days • Screening logs kept for only 1 month of the year • sites to be notified of the randomly selected month in advance. • Use of an Interactive Voice Randomisation System (IVRS) in China

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

5. Study Outline 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 R Standard best practice stroke unit care IntensiveBP 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) Repeat CT scans 24 hrs in selected patients Vital signs and BP over 7 days 28 day and 3 month follow-up

6. Sample Size • 2800 patients from 140+ sites •  90% power for: • 14% RRR in death/dependency in active vs control • 20% RRR in (50%) randomised <4 hours

7. Network UK 27 centres Europe Austria, Finland, France, Germany, Portugal, Spain, Switzerland, The Netherlands, Italy, Poland 64 centres China 49 centres USA (Rochester) 1 centre India /Pakistan 13 centres Brazil 9 centres Chile 6 centres Australia 14 centres Argentina 6 centres

8. Inclusion Criteria • Age 18 years or above • Acute spontaneous ICH (history and CT) • At least two systolic BP 150-220 mmHg, recorded ≥2 min 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

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

10. Exclusion Criteria (cont.) • 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

11. Eligibility To be eligible for INTERACT2: • All inclusion criteria questions must be answered “YES” • All exclusion criteria questions must be answered as “NO”

12. Randomisation system Patients are stratified according to: time since stroke onset (0-4 vs. 4-6 hours), site and country of recruitment

13. Schedule of Assessments

14. Outcomes • Primary – composite of death or dependency (ie score 3–5 on the modified Rankin Scale [mRS]) at 90 days • Secondary: • Key – primary endpoint in patients <4 hrs of ICH onset • Others • Death • Dependency; • Disability on the mRS • HRQoL (using the EuroQoL and health utility score EQ5D) • Recurrent stroke after 24 hrs of initial ICH • Other major CV events (myocardial infarction or sudden death) • Need for permanent residential care • Duration of initial hospitalisation.

15. Summary • INTERACT2 has been designed to provide a definitive answer to the management of elevated BP in patients with acute ICH • If successful, thousands of patients could benefit, with associated major health gains

16. Acknowledgements • Patients and families • Participating hospitals and staff • Many project staff in multiple countries • Funding: • National Health and Medical Research Council of Australia • The George Institute for Global Health

17. Acknowledgements Executive committee: Craig Anderson (Principal Investigator), John Chalmers (Chair), HisatomiArima, Stephen Davis, Emma Heeley, Yining Huang, Richard Lindley, Bruce Neal, Mark Parsons, Christian Stapf, Christophe Tzourio and Jiguang Wang. China steering committee: Yining Huang, Jiguang Wang, Liying Cui, Shengdi Chen, Zhenguo Liu, Chuanzhen Lu, Qidong Yang, En Xu, Jingfen Zhang, Chaodong Zhang, Shizheng Wu and Xining Yan Chen European advisory board: Austria – Ronny Beer, Erich Schmutzhard; Belgium – Patricia Redondo; Finland – MarkkuKaste, LauriSoinne, TurgutTatlisumak; France – Christian Stapf, Christophe Tzourio, Eric Vicaut; Germany – KatjaWartenberg; Italy – Stefano Ricci; Netherlands – Karin Klijn; Portugal – Jose´ Ferro; Spain – Angel Chamorro; Switzerland – Marcel Arnold, Urs Fischer; UK – Tom Robinson. Operations committee: Emma Heeley, Candice Delcourt. International coordinators: Michelle Leroux, Tara Sasse, Jun Hata, Gouyjen, Tina Cheung, Cathy Boreham, Sarah Leighton. Regional coordinators: Americas – Alejandro Rabinstein; Argentina – Conrado J. Estol, Mariana Zimmermann; Brazil – Gisele Silva, Joyce Marinho; Chile – Pablo Lavados; China – Jian Sun, Nan Li, Zhao Yan, Chen Xiaoying; France – Sofiane Kabla, Cecile Dert; India –K Mallickarjuna, Najam Hassan, JeyarajPandian. DSMB members: John Simes (Chair), Marie-Germaine Bousser, Graeme Hankey, KonradJamrozik (deceased in 2010), Claiborne Johnston and Li Shunwei. Statisticians: Laurent Billot, Stephane Heritier and Qiang Li.