SPACE-2 Why was the protocol modification not successful? Peter A. Ringleb Department of Neurology

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1 SPACE-2 Why was the protocol modification not successful? Peter A. Ringleb Department of Neurology

2 Disclosures Peter A. Ringleb, MD Professor of Vascular Neurology and head of the Stroke service at the University hospital Heidelberg (GER) Member of the WSO, ESO, DGN, DSG, DGNI, DEGUM Secretary of the German Stroke Society National Coordinator of SITS Clinical Coordinator of SPACE, Member of the Steering-Committee of SPACE-2 Member of the Steering-Committee of ECASS4 Member of the Ethics Committee of the Medical Faculty of Heidelberg Lecture-fees and travel-expenses from Bayer, Boehringer Ingelheim, Daiichi Sankyo, Ferrer, Glaxo Smith Kline, Lilly, Paion, Sanofi MAC-C Dec 20

3 Agenda SPACE-2 Study background SPACE-2 design Initial Modified Trial problems MAC-C Dec 20

4 NEJM, May 16, 2008

5 Stent-protected Angioplasty in Asymptomatic Carotid Artery Stenosis vs. Endarterectomy A three-arm Clinical Trial Reiff T et al., Int J Stroke (2009); 4: 294-9

6 n questions Whether CAS or CEA are superior to a modern medical therapy (OMT) in the primary prevention of ischemic stroke in patients with a severe asymptomatic carotid stenosis? Whether CAS is at least non-inferior to CEA in terms of safety and efficacy?

7 Design Investigator-initiated prospective, randomized, multicenter trial Three arms: Optimal medical treatment (OMT) CEA + OMT CAS + OMT about 0 certified centers N=3.640 patients with a follow-up of five yrs. (duration 8-9 yrs.) Funding by the German Ministry for Education and Research (BMBF, about 4 Mio )

8 Endpoints Safety endpoint: any stroke and death within 30 days Primary efficacy endpoint: any stroke or death between randomization and day 30 plus any ipsilateral ischemic stroke during 5 yrs Several secondary endpoints

9 Quality standards for study centers Neurological, vascular surgical and interventional competence Established cooperation between these groups All neurologists must have a NIHSS certificate Documentation (indication, outcome) of the last 40 CEA and CAS-procedures, confirmed by the cooperating neurologist Participation in CEA and CAS registries is mandatory

10 Randomization (Dec 20) Sep 09 Nov 09 Jul Sep Nov Jul Sep Nov Jul Sep Nov Jul Sep Nov Jul SPACE-2 randomization altes Design neues Design

11 Study Situation 01/20 32 centers 406 patients Possible explanations: Stenosis has to be treatable with both modalities Preference of patients not considered ~0 centers patients Some centers does have only one interventional discipline Randomization in a three-armed study design sometimes difficult to explain

12 Design Modification SPACE2-A CEA OMT SPACE-2 SPACE2-B CAS OMT Reiff T et al., Int J Stroke (20); 9: E-3

13 Stent-protected Angioplasty in Asymptomatic Carotid Artery Stenosis vs. Endarterectomy Since 20: Two two-arm Clinical Trials Reiff T et al., Int J Stroke (20); 9: E-3

14 Study scheme Decision by treating physician (and patient) SPACE2-A (n=1.636) SPACE2-B (n=1.636) Randomization (1:1) Randomization (1:1) CEA+OMT OMT CAS+OMT OMT

15 Expectations Simplification of recruitment process (also to acquire new centers) Enhancement of recruitment Smaller study population Lost of direct comparison of CEA / CAS

16 Sep 09 Nov 09 Jul Sep Nov Jul Sep Nov Jul Sep Nov Jul Sep Nov Jul SPACE-2 randomization altes Design neues Design Randomization (Jul 20)

17 Randomization (Jul 20) Feb Apr Jun Jul Aug Sep Okt Nov Dez Feb Apr Jun Jul 0 1,5 Pat/Ztr/Mon 1,75 Pat/Ztr/Mon 2 Pat/Ztr/Mon PatientenIST ZentrenSOLL ZentrenIST

18 SPACE-2 Early termination of the study Even after modification / simplification of the protocol, recruitment rate did not increase as expected (wished) Based on this observation funding was stopped by the German research foundation (DFG) One of the main-problems are enormous numbers of patients treated outside the trial MAC-C Dec 20

19 German QS, Carotid reconstruction EP: Stroke or death Asympt. CS (without contralat. stenosis) CEA CAS 2 /, % ( ) 35 / 2, % ( ) 155 /, % ( ) 42 / 2, % ( ) MAC-C Dec 20

20 SPACE-2 Early termination of the study Even after modification / simplification of the protocol, recruitment rate did not increase as expected (wished) Based on this observation funding was stopped by the German research foundation (DFG) One of the main-problems are enormous numbers of patients treated outside the trial Maybe also because of economic reasons OMT: ~ 0 CEA/CAS: ~ 6000 MAC-C Dec 20

21 N of patients MR CLEAN Recruitment Expected Observed Administration s decision to pay intervention only as part of the trial Dec July 20 Diederik Dippel, WSC 20, Istanbul MAC-C Dec 20

22 SPACE-2 Early termination of the study Even after modification / simplification of the protocol, recruitment rate did not increase as expected (wished) Based on this observation funding was stopped by the German research foundation (DFG) One of the main-problems are enormous numbers of patients treated outside the trial Maybe also because of economic reasons Discussion (with the DFG) about continuation of the Follow- Up-examinations are ongoing Participation in ACST-2 or ECST-2 left to the discretion of the centers, but supported in general by the SC MAC-C Dec 20

23 Thank you very much for your attention