The S troke O xygen S upplementation Study

1. The Stroke Oxygen Supplementation Study www.so2s.co.uk Chief Investigator: Prof. Christine Roffe Trial Manager: Dr Sarah Pountain North Staffordshire Combined Healthcare Trust Funded by National Institute For Research: Research for Patient Benefit

2. Hypoxia ABG [kPa] Saturation [%] Normal 12.6 ±0.1 97 ±2 Mild hypoxia 9.3<95 Moderate hypoxia8.0<92% Severe hypoxia 6.7<85 Life threatening 5.3<75

3. Oxygen saturation in acute stroke patients Roffe et al, Stroke 2003;34:2641-2645.

4. Unexpected nocturnal hypoxia in acute stroke patients Time spent with an oxygen saturation <90% at night 52% more than 5 minutes 23% more than 30 minutes 15% more than 1 hour Roffe et al, Stroke 2003;34:2641-2645

5. Post-stroke hypoxia is usually caused by complications 100 90 SpO2 (%) 80 • Airway Obstruction • Aspiration • Pneumonia • Pulmonary emboli • Fluid overload • Sleep apnoea 68 year old male with left hemiparesis and pneumonia.

6. Adverse effects of hypoxia after stroke Early deterioration 381 consecutive patients with acute stroke Oxygen saturation <90 doubles risk of early deterioration. Silva et al, Cerebrovasc Dis 2001;11(suppl 4):70

7. Adverse effects of hypoxia after stroke Increased mortality • N=153 assessed from arrival and during transfers till ward admission • Hypoxia defined as SpO2<90 for >10% of assessment phase • Oxygen saturation lowest during transfers • Hypoxic pts are more likely to have a history of chest problems • Hypoxia doubles mortality, but no longer significant if corrected for stroke severity • No effect on long-term disability Rowat et al. Cerebrovasc Dis 2006;21:166-172.

8. Adverse effects nocturnal hypoxia after stroke Increased level of disability £10 desaturations/h >10 desaturations/h Good, Stroke 1996;27:252-259 Silva,Cerebrovasc Dis 2001;11(suppl 4):70, Sandberg, JAGS 2001;49:391-397.

9. National and international Stroke Guidelines UK National Clinical Guidelines for Stroke Arterial oxygen concentration should be maintained within normal limits 2004 Give Oxygen to maintain oxygen saturation at or above 95% 2008 European Stroke Initiative Recommendations for Stroke Management 2-4L/min when indicated in 2003 Oxygen if saturation<92% in 2007 American Stroke Association Guidelines Oxygen if saturation <95% in 2003 and 2005 Oxygen if saturation </=92% in 2007 National Clinical Guidelines for Stroke. RCP 2004, 2008, NICE 2008, EUSI 2004, ESO 2007; ASA, Stroke. 2003;34(4):1056-83, 2005;36:916-23, 2007;38:1655-1711.

10. When to start oxygen?Views of British Stroke Physicians Arora et al, Br J Cardiol 2005;12:456-458.

11. Oxygen saturation on arrival in hospital Oxygen Saturation (%) Age (years) n=105 Mean age 74.0 years (SD 9.6 years) Mean oxygen saturation 96.3% (SD 1.6%) Stroke Oxygen pilot Study in progress, baseline demographic data,

12. Should we give oxygen to prevent hypoxia?

13. Experimental Evidence • 100% oxygen increases oxygen delivery to the ischaemic brain in mice • Infarct size at 2 days reduced by 45% • Shin, H. K. et al. Brain 2007 130:1631-1642 • 95% O2 reduced neurological deficit and infarct size in rats Liu et al J Cereb Blood Flow Metab. 2006;26:1274-84.

14. Selective high dose (45L/min) short burst oxygen supplementation • Methods— • acute stroke <12 h and perfusion-diffusion "mismatch" on MRI • RCT of high-flow oxygen via mask for 8 hours (n=9) vs room air (n=7) • Results— • Oxygen tended to improve stroke scale scores at 4 h and 1 week, and significantly at 24 h, but there was no significant difference at 3 months. • MRI lesion volumes were significantly reduced at 4 hours, but not subsequent time points. • Cerebral blood volume and blood flow within ischemic regions improved • More petechial hemorrhages (50% w oxygen vs 17% w room air) Singhal et al . Stroke. 2005;36:797-802.

15. Routine oxygen supplementation No oxygen Oxygen No oxygen Oxygen Oxygen No oxygen All strokes Mild strokes SSS>40 (top) Severe strokes SSS £ 40 (bottom) Ronning and Guldvog, Stroke 1999;30:2033-37.

16. Potential adverse effects of oxygen Masking of an important warning sign of underlying pathology Formation of toxic free radicals Stress imposed by the mask or cannula Drying of mucous membranes Hospital acquired infection through the plastic tubing Immobilization of the patient Unintended effects on staff attitude to the patient Respiratory depression in patients with severe COPD

17. Oxygen for Stroke • Oxygen is increasingly given to acute stroke patients • No uniform guidelines for the prescription of oxygen to acute stroke patients • Variation amongst clinicians of when oxygen supplementation should be given

18. SOS Study A multi-centre, randomised, open, blinded-endpoint study Routine oxygen treatment for 72 h after a stroke

19. Aims of SOS Study • Main Hypothesis Fixed dose oxygen treatment during the first 3 days after an acute stroke improves outcome. • Secondary hypothesis Restricting oxygen supplementation to night time only is more effective than continuous supplementation.

20. TheStrokeOxygenSupplementation Study Protocol

22. Eligibility for the study • Inclusion criteria • Adult patients with acute stroke • No definite indications or definite contraindications for O2 treatment • Within 24 hours of admission • Exclusion criteria • Potential indications for O2 treatment • O2 saturation on air <90% • dyspnoea • Medical indications for oxygen (PE, severe pneumonia, acute asthma) • Patients on long term oxygen for chronic lung disease • If the stroke is not the main clinical problem • Serious life threatening illness

23. Types of consent forSOS Study • Patient written consent • Relative/carer or legal representative consent • Independent Physician consent • Patient confirmation of consent (after recovery)

24. Baseline and Randomisation • Randomisation form • Baseline O2 saturation & demographics • Date & time of event • Glasgow Coma Scale • NIHSS • Predictors of outcome • Log on or phone to randomise • www.so2s.co.uk • Tel: 0300 123 0891 • Assigned to a treatment group

25. Treatment Groups • No routine O2 • O2 per nasal cannulae for 3 nights: • 3 L/min if O2 saturation at baseline is ≤ 93% • 2 L/min if O2 saturation at baseline is > 93% • Continuous oxygen per nasal cannulae for 72 hours • 3 L/min if O2 saturation at baseline is ≤ 93% • 2 L/min if O2 saturation at baseline is > 93%

26. 1 week post recruitment • Local, trained, research team member • 7 days ± 1 day after enrolment • Confirm diagnosis • Document death • NIHSS • Compliance with the intervention • Complications • Data entered online

27. 3, 6 & 12 month post recruitment • Centrally by SOS team • Questionnaire sent to patient • Deaths • Discharge status • Modified Rankin Score • Barthel ADL score • Nottingham EADL score • EuroQuol score • Memory • Sleep • Speech

28. Outcome Measures No. of patients with neurological deterioration Mortality Highest/lowest oxygen saturation during the first 72hr Modified Rankin score Quality of life Level of disability

29. Study Documentation

30. SOS Study File • SOS Study Contact Details • Study Documentation • Investigator Site Personnel & Signed Agreements • Regulatory/Ethics Committee • Subject Documentation • Safety Reporting • Data Collection • Study Monitoring & Reports • Correspondence

31. 1. SOS Study Contact Details • SOSStudy Manager Dr Sarah Pountain E-mail: sarah.pountain@northstaffs.nhs.uk Tel: 0300 123 0891 • SOSChief Investigator Dr Christine Roffe E-mail: christine.roffe@northstaffs.nhs.uk Tel: 0300 123 1465 Stroke Research Office, North Staffordshire Combined Healthcare NHS Trust, Holly Lodge, 62 Queens Road, Hartshill, Stoke-on-Trent, ST4 7LH. Tel: 0300 123 0891 • 24 HOUR RANDOMISATION http://www.so2s.co.uk • EMERGENCY CONTACT DETAILS Mobile No 07740 372852 (main) 07734 068408 (back-up)

32. 2. Study Documents • http://www.so2s.co.uk • Version updates – e-mail PI, announced on website • On site headed note paper - consent forms, patient information sheets and the GP letter • File Notes • Equipment Validation • Patient Document Tracking Log • SOPs

33. 3. Investigator Site Personnel • Delegation Log • Training Log • CVs & Job Description • Financial Information • CTA

34. 4. Regulatory/Ethics Committee • MHRA Approval • Oxygen Data Sheet • Ethics Application & Approval • R & D Approval • Safety updates • Reports • End of trial notification • Correspondence to/from ethics/MHRA

35. 5. Subject Documentation • Screening Log • Subject Enrolment/Identification Log • Signed consent forms

36. 6. Safety Reporting • Adverse Events – report on R&D-RF-SOS-001 (from website) fax and e-mail to Sponsor within 14 days • SAEs & SUSARs – notify study centre immediately, complete SAE form and fax to Study centre AND sponsor within 24 hours of becoming aware of the event. • Reporting of Safety Measures - notify study centre immediately – complete form R&D-RF-SOS-002 (from website) fax or e-mail to study centre AND sponsor, within 24 hours.

37. 7. Data Collection • Completing the CRF • Consent – types of, obtaining, consent procedure dialogue • Information sheets and consent forms • Randomising patient’s into SOS study • How to randomise using the web based system • Completing the week 1 follow up • Inputting the week 1 follow up • Long term follow up • Notification of death • Completed notification of death forms

40. Click on New Randomisation • Confirm your site • Select clinician • Identifying details - patient surname, forename, sex, DOB, Unit no. • Eligibility – time since admission, time since stroke, expected to die within 1 year from non-stroke related illness, indications for O2, contraindications for O2 • Patient details – date of stroke, time of stroke, O2 given in the ambulance (if yes how much), O2 given on arrival (if yes how much)

41. Medical History – COAD, other chronic lung problem, heart failure, IHD, AF • GCS • NIHSS • Prognostic factors - live alone?, independent in daily living, lift affect arm, walk unaided, O2 sat. at randomisation • Consent • Confirm all details • Check randomisation options

42. Go back

43. 1 Week follow up data input • Log into database from http://www.so2s.co.uk • Click on patient forms • Select relevant patient

44. Go back

45. Notification of death • In the event of death can you please complete the notification of death form for your records and complete the form on line. • To access the form online log onto the SOS website (http://www.so2s.co.uk). • Click on “Click here to randomise or enter data”. • Enter user name and password, select live as data type. • Select Patient forms to enter data. • Select the patient and click on View Details. • Select Notification of Death from the left hand side of the screen and click on View form. • Enter details, click on save. • Click on Exit. • Exit website, will automatically log out when website closed down.

46. 8. Study Monitoring & Reports • Final Study Reports • Interim Reports • Publications/Abstracts • Safety Updates and Reports • Initiation Visit Report • Visit Log • Close out Letter

47. 9. Correspondence • General Correspondence • SOS Newsletter • Minutes of Meetings

48. Study Contacts • SOSStudy Manager Dr Sarah Pountain E-mail: sarah.pountain@northstaffs.nhs.uk Tel: 0300 123 0891 • SOSChief Investigator Dr Christine Roffe E-mail: christine.roffe@northstaffs.nhs.uk Tel: 0300 123 1465 Stroke Research Office, North Staffordshire Combined Healthcare NHS Trust, Holly Lodge, 62 Queens Road, Hartshill, Stoke-on-Trent ST4 7LH

49. Trial Management Committee Trial Steering Committee Prof. Richard Lindley Prof. Martin Dennis Prof. Lalit Kalra Prof. Sian Prothero Jane Daniels Mrs Peta Bell • Dr Christine Roffe • Prof. Peter Jones • Prof. Peter Crome • Prof. Richard Gray • Mr Peter & Mrs Linda Handy (Strokes R Us) Patient Representatives Data Monitoring & Safety Committee • Peter & Linda Handy • Mrs Peta Bell • Prof. S Jackson • Prof. T Robinson • Dr Martyn Lewis International Advisory Committee Sponsor • Prof. Richard Lindley • North Staffordshire Combined Healthcare NHS Trust