Where are we with VIST currently? Hugh Markus, Chief Investigator Jennifer Lennon, Trial Manager VIST Investigator’s Meeting Monday 22nd September 2014 Mary Ward House Study Aim • To determine if stenting/angioplasty or best medical treatment is more effective at preventing recurrent events in symptomatic vertebral stenosis • Feasibility/pilot phase (N=100) – achieved July 2012 • NIHR HTA have just funded extension to N=540 in UK and Europe. • 2nd Netherlands only trial – VAST- co-ordinated protocols Inclusion Criteria • Vertebrobasilar non-disabling stroke or TIA in last 3 months but in view of risk profile we recommend to treat as soon as possible after symptoms • Vertebral stenosis ≥50% as per MRA, CTA or IAA • Stenosis resulting from presumed atheromatous disease • Stenting considered technically feasible • Women or men aged >20 years of age • Patient able to provide written informed consent and willing to be randomised to either treatment • If randomised to stenting arm, will be done within two weeks of randomisation Exclusion Criteria • Patients unwilling or unable to give informed consent • Patients unwilling to accept randomisation to either treatment arm • Vertebral stenosis caused by acute dissection as this has a different natural history and usually spontaneously improves • Patients in whom vertebral stenting is felt to be technically not feasible e.g. access problems • Previous stenting in the randomised artery • Pregnant and lactating women Randomisation • Web-based randomisation service provided by King’s College Institute of Psychiatry • Patients randomised to stent or best medical treatment • Randomisation stratified by location of stenosis • Extracranial (V1-3) • Intracranial (V4) Study outline • Consent and Baseline assessment • +/- stenting/angioplasty • 1 month – hospital • 6 months – telephone • 1 year – hospital with repeat CTA/MRA • 2 year and annually until study end – telephone Outcomes Primary Fatal or non-fatal stroke in any arterial territory (including periprocedural stroke) during trial follow up Outcomes Secondary endpoints • Fatal or non-fatal stroke in any arterial territory (including periprocedural stroke) at three months post-randomisation • Posterior circulation stroke (including periprocedural stroke) during follow-up • Periprocedural stroke or death (within 30 days of procedure) • Posterior circulation stroke and TIA during follow-up • Any disabling stroke (defined by a Rankin >3) during follow-up • Death of any cause during follow-up • Restenosis in treated artery during follow-up Notice risk is highest early on No Stenosis Extracranial Stenosis Intracranial Stenosis Kaplan Meier curves showing risk of recurrent stroke alone and of the combined endpoint of recurrent stroke and TIA from first event. Blue line: patients with no stenosis; gray line: patients with extracranial stenosis; green line: patients with intra-cranial stenosis; red line: patients with any stenosis Reference: Gulli et al. Stroke 2013. DOI: 10.1161/STROKEAHA.112.669929. Copyright © 2013 American Heart Association, Inc. All rights reserved. • VIST has undergone a number of changes since the last Investigator’s Meeting (October 2011): – – – – – Funder Sponsor Protocol How data are collected International collaborators From Pilot to Definitive Study • Awarded grant from new funder in July 2012 to take VIST to a full study (n=540): National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme • End of recruitment currently planned 28 February 2016 • Increased recruitment targets & centres expected (UK, Europe, ROW) Amendments & Protocol Updates Initial Updates: Substantial Amendment 5 (Jan 2013) • Changes to the protocol as suggested by the HTA  Only include patients within three months after symptoms (either non-disabling VB stroke or TIA) so that we can treat them during their period of high recurrent stroke risk  Ensure that patients randomized can be stented within two weeks • Modified our Trial Steering & Data Monitoring Committees to include more independent members • Also added Health Economics and eCRF data collection Substantial Amendment 6 • REC approved August 2013 • Summary of key change(s): – – – – Made it clear that BOTH arms will receive BMT Defined “non-disabling stroke” (mRS<4) w.r.t. inclusion criteria Increased rigidity of imaging review requirements Plan to analyse intra- and extracranial separately as well as together – Clarified co-enrollment with other RCTs in ethics application • Acceptable where the intervention does not interfere with the assessment and efficacy in VIST, and vice versa Substantial Amendment 7 • REC approved February 2014 • Summary of key change(s): – Change in Sponsorship – Other minor clarifications to original Ethics application: • Aligned research investigation requirements and non-clinical research related interviews with the Protocol • No minimum time to consent, i.e. treat as soon as possible • Extend recruitment beyond UK, i.e. international trial • Add process for manual randomisation in event of system failure to Protocol Substantial Amendment 8 • REC approved July 2014 • Summary of key change(s): – Allow the use of predicted Modified Rankin score at randomisation * Non-disabling is defined as having a score on the modified Rankin Scale of ≤3 at time of randomisation†. If modified Rankin Score is ≥4, disability must be due to non-stroke related condition. NEW † If you predict that the patient will have a modified Rankin Score of ≤3 by 3months post-stroke, it is acceptable to randomise. • We are now working to Protocol Version 8.0 – Please ensure you are all working to the latest version! Addition of Health Economics Health Economics • Cost and cost-effectiveness of VA angioplasty/stenting vs BMT during the ‘within-trial’ period and over expected lifetime of the patient • Anticipate 80% of pts to be alive after 5yrs • As we anticipate that UK will recruit most patients (~388/540), costs will be assessed from the perspective of NHS and personal social services (PSS) in the UK, based on resource use data collected from UK patients only • Data collected: Residence, Admission Details, EuroQOL (EQ5D5L), Patient Diaries (Year 1 only) From Paper to eCRF eCRF • To improve data collection and quality • InferMed MACRO 4.0 – Built & maintained by the CTU at the Institute of Psychiatry, Kings College London – Rolled-out to centres in December 2013 – New Advanced Randomisation Service also released in line with this • All active sites now have access to both systems Paper CRF • Continue to complete and file for monitoring purposes • Reduces amount of data to be faxed to CTO: – Consent Form plus Contact Details Form • This is to allow contact with patients for follow-up – Patient Diaries – Death Certificates, SAE & Event Forms – Imaging Reports & supporting documentation helpful • Please ensure that you are using the latest version – Always download from study website: www.vist.org.uk – Both UK and non-UK centre versions available From London to Cambridge • CI moved to Cambridge in August 2013 • Sponsorship transferred in December 2013 • Joint Sponsors: Cambridge University Hospitals NHS Trust & University of Cambridge • New Contracts issued to all centres • New Trial Manager now appointed • Trial office will move to Cambridge end of October 2014 • New email address and contact tel/fax will be distributed • In the meantime, please continue to use the usual contacts • New-look website also to be released • Same URL: www.vist.org.uk Recruitment & Centre Status Recruitment Update Target = 540 Current total = 170 If each centre recruits just 1 patient per month we’ll meet our target! 175 No. of Patients 150 125 100 75 50 25 0 Oct-15 Jun-15 Feb-15 Oct-14 Jun-14 Feb-14 Oct-13 Jun-13 Feb-13 Oct-12 Jun-12 Feb-12 Oct-11 Jun-11 Feb-11 Oct-10 Jun-10 Feb-10 Oct-09 Jun-09 Feb-09 Oct-08 Recruitment Period Centres in Study • 15 sites open in the UK • • • • • • • • • • • • • • • St George’s University of London Addenbrooke’s, Cambridge The John Radcliffe, Oxford Royal Hallamshire, Sheffield Kings College London The Walton Centre Liverpool Freeman Hospital Newcastle UCLH London Royal Preston Lancashire University Hospital of North Staffordshire Leeds General Hospital Charing Cross Hospital London Frenchay North Bristol Nottingham The Royal London • 1 site now open in ROW: • • Hong Kong In progress: • UK: • Southend • QEH Birmingham • Cardiff UHW • Europe/ROW: • Australia • Germany • Austria Baseline Data Overview Age & Gender 70 160 140 50 Patients Randomised Patients Randomised 60 40 30 20 10 120 100 80 60 40 20 0 50 and under 51 – 60 61 – 70 71 – 80 Over 80 0 Male Age at Randomisation Age (at randomisation) Mean (SD) Range 50 and under 51 – 60 61 – 70 71 – 80 Over 80 Female Gender 68 44-86 9 34 61 50 15 % 5 20 36 30 9 Sex Male Female 140 29 % 83 17 Risk Factors 120 No. of Randomised Patients 100 80 60 40 20 0 Treated hypertension Angina in last 6 months Previous MI Atrial fibrillation Risk Factor at Entry Diabetes Smoking History Treated hyperlipidemia Modified Rankin 35 60 Non-stroke disability Number of Randomised Patients % of Randomised Patients 30 25 20 15 10 5 0 Stroke disability 50 40 30 20 10 0 Modified Rankin Score at Randomisation Modified Rankin Score at Randomisation Randomisation Event 120 110 Number of Patients 100 80 56 60 40 20 0 Stroke TIA Randomising Event Location of Stenosis Time from Event to Randomisation By event type: In 2013, criteria changed to include patients within 3 months of their event only Time since Event (days) Over time: Time from Randomisation to Procedure In 2013, criteria changed to perform procedure <14 DAYS from randomisation 2 x 2013 cases were randomised PRIOR TO NEW INCLUSION CRITERIA 4 x 2013/14 cases were randomised POST NEW INCLUSION CRITERIA -> PDs Crossovers Crossover Forms Crossovers Over Time Central Imaging Review: Results Entry Imaging Received (as of 1 Sept) Entry Imaging Reviewed (as of 1st Sept) Entry Imaging Received Pending Review (as of 1st Sept) n = 170 161 151 10 ≥50% Stenosis seen on PRE-RANDOMISATION/ENTRY imaging reviewed MRA only CTA only MRA and CTA MRA and/or CTA plus IA, or IA alone 134 51 43 29 11 st ≥50% Stenosis NOT seen on PRE-RANDOMISATION/ENTRY imaging reviewed 5 Reviewers Comments: All 5 cases had a pre-randomisation CTA showing <50% stenosis; should never have been randomised. % Stenosis EQUIVOCAL on PRE-RANDOMISATION/ENTRY imaging reviewed 12 MRA only 6 CTA only 4 MRA and CTA 1 CTA and IA 1 Reviewers Comments: Where MRA only performed, I would not have randomised without a confirmatory CTA. Where both MRA and CTA were done, the CTA showed no stenosis. Where CTA only performed, inadequate imaging was performed in some cases. Central Imaging Review: Feedback • Inadequate or incomplete imaging received • Source data needed; Non-diagnostic studies received • Ensure imaging sent shows the stenotic vessel/location • E.g. Intracranial imaging for V4 stenosis, neck vessel imaging for V1 stenosis • Ensure MDT reviews cases & comes to agreement before randomisation • Slices to Dr Clifton or Dr Küker ahead of randomisation if needed • Do CTA to confirm if not clear on MRA • If still not sure, need to do IA • Afternoon session will go into more detail (Dr Andy Clifton) We are here to help! Pre-randomisation Eligibility Review Monthly Site Calls Newsletters & updates Potential Participant Screening Checklist Online Guidance Documents Researchers teleconferences Contact Us! Chief Investigator Professor Hugh Markus [email protected] Trial Coordinator Mrs Jennifer Lennon (Ms Ana Boschoff) [email protected] T: 0208 725 5403 F: 0208 725 2950 Lead Interventionists Dr Andrew Clifton [email protected] Dr Wilhelm Küker [email protected] Study Website www.vist.org.uk Please get in touch if you have ANY questions!