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| [ ...Back to search results ] | [ Print-friendly version ] |
| Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke |
| ISRCTN | ISRCTN47823388 |
| ClinicalTrials.gov identifier | |
| Public title | Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke |
| Scientific title | Safety and tolerability of clopidogrel when added to aspirin and dipyridamole in high risk patients with recent ischaemic stroke: a randomised controlled trial |
| Acronym | TARDIS |
| Serial number at source | 1.1 |
| Study hypothesis |
To perform a randomised trial assessing the efficacy, safety and tolerability of adding clopidogrel to aspirin and dipyridamole in patients with recent ischaemic stroke or transient ischaemic attack (TIA) and who are at high risk of recurrence. The study will comprise a start-up phase of 350 patients to then expand into a larger trial of 5000 patients assessing the efficacy, safety and health economics of this approach. A secondary hypothesis is that ordinal vascular outcomes will be superior to binary events; the trial is the first to be designed using these outcomes, this allowing both the frequency and severity of events to be assessed in one measure. Ordinal outcomes include bleeding, adverse events, stroke, myocardial infarction (MI), composite vascular events, and take the form: fatal event/non-fatal severe event/mild event/no event. Conventional binary outcomes will also be measured.
Please note that as of 25/03/10 this record has been updated. All updates can be found in the relevant field with the above update date. |
| Ethics approval | South East MREC approved the protocol (v1.1) on the 9th of January 2009. Ammendments to the protocol (v1.2) were approved on the 16th of June 2009 |
| Study design | Multicentre parallel group prospective randomised open-label blinded-endpoint controlled trial |
| Countries of recruitment | United Kingdom |
| Disease/condition/study domain | Ischaemic stroke, transient ischaemic attack (TIA) |
| Participants - inclusion criteria |
Current information as of 25/03/10:
Adults at high risk of recurrent ischaemic stroke: 1. Acute non-cardioembolic ischaemic stroke (<48 hours of onset). All strokes must have motor weakness or dysphasia at the time of randomisation. 2. Acute TIA (<48 hours of onset) with one or more of: crescendo TIA (>1 TIA within 1 week), and/or admitted on dual antiplatelet therapy (aspirin/dipyridamole, aspirin/clopidogrel, clopidogrel/dipyridamole), and/or with an ABCD2 score >4. All TIAs must have motor weakness and/or dysphasia lasting at least 10 minutes 3. Meaningful consent, or consent from a relative, carer or legal representative if the patient is unable to give meaningful consent (e.g. in cases of dysphasia, confusion, or reduced conscious level) Initial information at time of registration: Adults of either sex at high risk of recurrent ischaemic stroke: 1. Acute non-cardioembolic ischaemic stroke (less than 48 hours of onset) 2. Acute TIA (less than 48 hours of onset) with one or more of: crescendo TIA (greater than one TIA within 1 week), and/or admitted on dual antiplatelet therapy (aspirin/dipyridamole, aspirin/clopidogrel, clopidogrel/dipyridamole), and/or with an ABCD2 score greater than 5 (stroke rate at 13 weeks greater than 10%) |
| Participants - exclusion criteria |
Current information as of 25/03/10:
1. Age <50 2. Motor weakness or dysphasia lasting <10 minutes 3. Pure sensory, vertigo or dizziness, speech or visual disturbance symptoms without weakness or dysphasia 4. Patients with contraindications to, or intolerance of, aspirin, clopidogrel or dipyridamole 5. Patients with definite need for treatment with clopidogrel (e.g. recent MI) 6. Pre-morbid dependency (mRS>2) 7. No enteral access 8. Parenchymal haemorrhagic transformation (PH I/II), subarachnoid haemorrhage or other non ischaemic cause for weakness 9. TIA not fulfilling inclusion criteria 10. Definite need for full dose oral (e.g. warfarin) or parental (e.g. heparin or glycoprotein IIb IIIa inhibitors) anti- coagulation. NB Low dose heparin for DVT prophylaxis is allowed. 11. Received thrombolysis within the last 30 hours 12. Presumed cardioembolic stroke (e.g. AF, recent MI, or other conditions need for anticoagulation) 13. Severe high BP (BP>185/110 mmHg) 14. Known haemoglobin less than 10g/dL 15. Known platelet count less than 100 x 109 /L 16. Known white cell count less than 3.5 x 109 /L 17. Bleeding within 1 year (e.g. peptic ulcer, intracerebral haemorrhage) 18. Planned surgery during 3 month follow-up (e.g. carotid endarterectomy) 19. Concomitant acute coronary syndrome 20. Stroke secondary to a procedure (e.g. carotid or coronary intervention) 21. Coma (GCS<8) 22. Non-stroke life expectancy <6 months 23. Dementia 24. Participation in another drug trial concurrently or within 30 days (Patients may be randomised into observational studies or non-drug trials) 25. Not available for follow-up e.g. no fixed address, overseas visitor 26. Females of childbearing potential, pregnancy or breastfeeding Note: Clopidogrel will be stopped around procedures that become necessary after enrolment Initial information at time of registration 1. Aged less than 40 years 2. Motor weakness lasting less than 30 minutes (pure sensory, vertigo or dizziness, speech or visual disturbance symptoms without weakness are excluded) 3. Patients with contraindications to, or intolerance of, aspirin, clopidogrel or dipyridamole 4. Pre-morbid dependency (modified Rankin Scale [mRS] greater than 3) 5. No enteral access 6. Parenchymal haemorrhagic transformation (PH I/II), subarachnoid haemorrhage or other non-ischaemic cause for weakness 7. TIA not fulfilling inclusion criteria 8. Definite need for, or currently on triple antiplatelet therapy or anticoagulation 9. Indication for, or received (in last week), thrombolysis 10. Presumed cardioembolic stroke (e.g. atrial fibrillation [AF], recent MI, or other conditions need for anticoagulation) 11. Severe high blood pressure (BP) (greater than 185/110 mmHg) 12. Bleeding within 1 year (e.g. peptic ulcer, intracerebral haemorrhage) 13. Planned surgery during 3 month follow-up (e.g. carotid endarterectomy) 14. Concomitant acute coronary syndrome 15. Stroke secondary to a procedure (e.g. carotid or coronary intervention) 16. Planned surgery during first month post stroke (e.g. carotid endarterectomy) 17. Coma (Glasgow Coma Scale [GCS] less than 8) 18. Non-stroke life expectancy less than 6 months 19. Dementia 20. Participation in another drug trial concurrently or within 30 days (patients may be randomised into observational studies or non-drug trials) 21. Not available for follow-up, e.g. no fixed address, overseas visitor 22. Females of childbearing potential, pregnancy or breastfeeding Note: Clopidogrel will be stopped around procedures that become necessary after enrolment |
| Anticipated start date | 01/03/2009 |
| Anticipated end date | 01/03/2017 |
| Status of trial | Ongoing |
| Patient information material | Not available in web format, please use the contact details below to request a patient information sheet |
| Target number of participants | Start-up phase: 350; main phase: 5000 |
| Interventions | Aspirin (loading dose 300 mg, then 75 mg daily), clopidogrel (loading dose 300 mg, then 75 mg daily) and dipyridamole (modified release 200 mg twice daily) versus dual antiplatelet therapy (aspirin and dypyridamole, doses as above) randomised 1:1. Dysphagic patients with enteral access will take crushed aspirin (or rectal aspirin), crushed or liquid dipyridamole (75 mg three times daily [tds]), and crushed clopidogrel (if so randomised). Patients having a headache on dipyridamole will have the dose weaned up from daily MR 200 mg or standard release 75 mg once daily [od] to MR 200 mg twice daily [bd]. Fixed dose combinations of aspirin and dipyridamole can also be used. Open-label clopidogrel will be given for 30 days on top of routine AD (to cover the period of maximum risk of recurrence) and standard ‘best care’ (including lifestyle advice, BP and lipid lowering). Patients will be recommended to take gastro-prophylaxis against upper gastrointestinal bleeding (proton pump inhibitor/histamine 2 receptor antagonist + H. pylori eradication), as is standard. |
| Primary outcome measure(s) | The trial will assess ordinal stroke severity at 90 days assessed as a level ordinal outcome: mRS 6 = fatal-5-4-3-2-1-0-TIA-no stroke; this approach allows for smaller sample sizes than for binary outcomes such as stroke/no stroke. The start-up phase will also assess ordinal bleeding (fatal/major/minor/none) at 35 days (end of treatment) as adjudicated by an independent blinded panel. |
| Secondary outcome measure(s) |
1. Secondary outcomes at 35 and 90 days:
1.1. Binary stroke 1.2. Ordinal stroke (fatal stroke/non-fatal stroke/no stroke) 1.3. Binary myocardial infarction 1.4. Ordinal myocardial infarction (fatal MI/non-fatal MI/no MI) 1.5. Binary composite vascular outcome (non fatal MI and stroke, vascular death) 1.6. Ordinal composite vascular outcome 1.7. Composite stroke, TIA, acute coronary syndromes and all cause death 2. Secondary outcomes at 90 days: 2.1. Function (modified Rankin Scale [mRS], Barthel Index) 2.2. Cognition (Telephone Interview for Cognitive Status [TICS]/animal naming) 2.3. Quality of life (EuroQoL/EQ-5D instrument) 2.4. Mood (Zung) 2.5. Disposition (home, institution, dead) 2.6. Days at home 2.7. Economic activity 3. Tolerability: Proportion of patients completing 28 days of randomised treatment 4. Feasibility: Recruitment rate per week 5. Safety measures at 35 and 90 days: 5.1. Death 5.2. Binary major bleeding (fatal, symptomatic, causing fall in haemoglobin of greater than 2 g/l, or leading to transfusion of greater than 2 units of blood/red cells) 5.3. Binary minor bleeding (e.g. bruising) 5.4. Binary all bleeding 5.5. Symptomatic intracerebral haemorrhage 5.6. Major extracranial bleeding 5.7. Binary serious adverse events 5.8. Ordinal adverse events (fatal/serious/other/none) 5.9. Full blood count (at 35 days) 5.10. Thrombotic thrombocytopenic purpura 5.11. Granulocytopenia Data from two substudies will power substudies within the future main trial: 1. Transcranial Doppler: TCD recordings will be performed from the middle cerebral artery (MCA) at baseline and day 3 ± 1 2. Platelet function: Platelet expression of P-selectin will be used to monitor platelet effects in patients. Blood will be taken from all patients at baseline and day 7 ± 1. |
| Sources of funding | British Heart Foundation (BHF) (UK) |
| Trial website | http://www.tardistrial.org |
| Publications | |
| Contact name | Prof Philip Bath |
| Address |
Institute of Neuroscience
Division of Stroke Medicine Clinical Sciences Building City Hospital Campus |
| City/town | Nottingham |
| Zip/Postcode | NG5 1PB |
| Country | United Kingdom |
| Tel | +44 (0)115 823 1765 |
| Fax | +44 (0)115 823 1767 |
| philip.bath@nottingham.ac.uk | |
| Sponsor | University of Nottingham (UK) |
| Address |
Research Innovation Services
King's Meadow Campus Lenton Lane |
| City/town | Nottingham |
| Zip/Postcode | NG7 2NR |
| Country | United Kingdom |
| Tel | +44 (0)115 951 5679 |
| Fax | +44 (0)115 951 3633 |
| paul.cartledge@nottingham.ac.uk | |
| Sponsor website: | http://www.nottingham.ac.uk/ |
| Date applied | 24/10/2008 |
| Last edited | 25/03/2010 |
| Date ISRCTN assigned | 23/01/2009 |
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