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

Peter A. Ringleb Department of Neurology

SPACE-2

Why was the protocol modification not

successful?

MAC-C Dec 2014

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 2014

Agenda

SPACE-2 • Study background • SPACE-2 design – Initial – Modified • Trial problems

A three-arm Clinical Trial

Stent-protected Angioplasty

in Asymptomatic

Carotid Artery Stenosis

vs. Endarterectomy

Main 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?

Design

• Investigator-initiated prospective, randomized, multicenter trial

• Three arms: Optimal medical treatment (OMT)

CEA + OMT

CAS + OMT

• about 100 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 €)

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

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

Randomization (Dec 2012)

0 100 200 300 400 500 600 Sep 09 Nov 09 Jan 10 Mrz 10 Mai 10 Jul 10 Sep 10 Nov 10 Jan 11 Mrz 11 Mai 11 Jul 11 Sep 11 Nov 11 Jan 12 Mrz 12 Mai 12 Jul 12 Sep 12 Nov 12 Jan 13 Mrz 13 Mai 13 Jul 13 Sep 13 Nov 13 Jan 14 Mrz 14 Mai 14 Jul 14 SPACE-2 randomization

• 32 centers • 406 patients

• Possible explanations:

– Stenosis has to be treatable with both modalities – Preference of patients not considered

– Some „centers“ does have only one interventional discipline

– Randomization in a three-armed study design sometimes difficult to explain

Study Situation 01/2013

• ~100 centers • 3.640 patients

SPACE2-A

OMT CEA

SPACE2-B

OMT CAS

SPACE-2

Design Modification

Reiff T et al., Int J Stroke (2014); 9: E12-3 www.space-2.de

Stent-protected Angioplasty in Asymptomatic

Carotid Artery Stenosis vs. Endarterectomy

Since 2013: Two two-arm Clinical Trials

Reiff T et al., Int J Stroke (2014); 9: E12-3 www.space-2.de

OMT

SPACE2-A (n=1.636)

CEA+OMT Randomization (1:1)

SPACE2-B (n=1.636)

CAS+OMT OMT Randomization (1:1)

Decision by treating physician (and patient)

• Simplification of recruitment process (also to acquire new centers)

• Enhancement of recruitment

• Smaller study population

• Lost of direct comparison of CEA / CAS

0 100 200 300 400 500 600 Sep 09 Nov 09 Jan 10 Mrz 10 Mai 10 Jul 10 Sep 10 Nov 10 Jan 11 Mrz 11 Mai 11 Jul 11 Sep 11 Nov 11 Jan 12 Mrz 12 Mai 12 Jul 12 Sep 12 Nov 12 Jan 13 Mrz 13 Mai 13 Jul 13 Sep 13 Nov 13 Jan 14 Mrz 14 Mai 14 Jul 14 SPACE-2 randomization

altes Design neues Design

Randomization (Jul 2014)

0 5 10 15 20 25 30 35 40 45 50 Jan 13 Feb 13 Mrz 13 Apr 13 Mai 13 Jun 13 Jul 13 Aug 13 Sep 13 Okt 13 Nov 13 Dez 13 Jan 14 Feb 14 Mrz 14 Apr 14 Mai 14 Jun 14 Jul 14 0 200 400 600 800 1000 1200 1400 1600 1800

MAC-C Dec 2014

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 2014

German QS, Carotid reconstruction

EP: Stroke or death 2012 2013

Asympt. CS (without contralat. stenosis) CEA 142 / 11,975 1.2% (1.0-1.4) 155 / 12,096 1.3% (1.1-1.5) CAS 35 / 2,036 1.7% (1.2-2.4) 42 / 2,452 1.7% (1.3-2.3) www.sqg.de/ergebnisse/leistungsbereiche/karotis-rekonstruktion.html

MAC-C Dec 2014

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€

MAC-C Dec 2014

MR CLEAN

Recruitment 0 50 100 150 200 250 300 350 400 450 500 N of patients Expected Observed

Dec 2010 Jan 2013 July 2014

Diederik Dippel, WSC 2014, Istanbul

Administration‘s decision to pay intervention only as part of the trial

MAC-C Dec 2014

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