Clinical trial NCT00097669: VITATOPS: A Study of VITAmins TO Prevent Stroke
Official title: VITATOPS - A Study of VITAmins TO Prevent Stroke
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Stroke
Transient Ischemic Attack
Keywords: VITATOPS
stroke
prevention
multivitamins
homocysteine
Lead sponsor: VITATOPS
Sponsor class: OTHER_GOV
Collaborators: name: National Health and Medical Research Council, Australia
name: National Heart Foundation, Australia
name: Medical Health Research Infrastructure Council, Australia
First posted: 2004-11-25
Enrollment: 8164
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The VITATOPS study is a multi-center, randomized, double blind, placebo-controlled secondary stroke prevention trial to determine whether the addition of vitamin supplements (B12 500 ug, B6 25 mg, Folate 2 mg) to best medical/surgical management (including modification of risk factors) will reduce the combined incidence of recurrent vascular events (stroke, myocardial infarction) and vascular death in patients with recent stroke or transient ischemic attack (TIA). All patients presenting to one of the participating neurologists or general physicians within seven months of stroke (ischemic or hemorrhagic) or TIA (eye or brain) are eligible for this trial. Eligible patients will be randomized in a double-blind fashion to receive multi-vitamins or placebo, 1 tablet daily. The primary outcome event is the composite event "stroke, myocardial infarction, or death from any vascular cause", whichever occurs first. Our target is to recruit a total of 8,000 patients over the next two years with a median follow-up of 2.5 years. Recruitment to the trial began in November 1998 and is planned to continue until December 2005. We aim to complete final follow-up by the end of 2006. However, the Steering Committee will be flexible in dictating the need for ongoing recruitment and continuing follow-up, depending on the overall rate of the primary outcome event in the entire cohort at each interim analysis.

Detailed description: Background: Epidemiological studies suggest that raised plasma concentrations of total homocysteine (tHcy) may be a common, causal and treatable risk factor for atherothromboembolic ischemic stroke, dementia and depression. Although tHcy can be lowered effectively with small doses of folic acid, vitamin B12 and vitamin B6, it is not known whether lowering tHcy, by means of multivitamin therapy, can prevent stroke and other major atherothromboembolic vascular events, dementia and depression.

Purpose: To determine whether vitamin supplements (folic acid 2 mg, B6 25 mg, B12 500 ug) reduce the risk of stroke, other serious vascular events, dementia and depression in patients with recent stroke or transient ischemic attacks of the brain or eye (TIA).

Methods: An international, multi-center, randomized, double-blind, placebo-controlled clinical trial.

Subjects: Patients with stroke or TIA in the previous 7 months.

Primary outcome measure: Non-fatal stroke, non-fatal myocardial infarction, or death due to vascular causes.

Secondary outcome measures: TIA, Revascularisation procedures, Dementia, Depression.

Sample size calculation: To reliably identify a 15% reduction in relative risk of the primary outcome event from 8% to 6.8% per year with an alpha of 0.05 and power of 80%, 8,000 patients need to be randomized and followed-up for an average of two years.

Current progress: As of November, 2004, more than 4,400 patients have been randomized in 73 centers in 19 countries in five continents: Australia, Austria, Belgium, Brazil, Hong Kong, Italy, Malaysia, Moldova, Netherlands, New Zealand, Pakistan, Philippines, Portugal, Republic of Georgia, Serbia \& Monte Negro, Singapore, Sri Lanka, United Kingdom, and United States.

VITATOPS aims to recruit and follow up 8,000 patients between 2000 and 2006, and provide a reliable estimate of the safety and effectiveness of dietary supplementation with folic acid, vitamin B12, and vitamin B6 in reducing recurrent serious vascular events, dementia and depression among a wide range of patients with stroke and TIA.

Eligibility criteria: Inclusion Criteria:

* Patients presenting within seven months of stroke (ischemic or hemorrhagic) or TIA
* Agree to take study medication
* Be geographically accessible for follow-up
* Provide written informed consent

Exclusion Criteria:

* Taking folic acid or B6 on medical advice
* Use of vitamin supplements containing folate, B6 or B12 (unless patient agrees to take study medication instead of the vitamin supplements which they usually take)
* Taking Methotrexate for any reason
* Pregnancy or women of child-bearing potential who are at risk of pregnancy
* Limited life expectancy

Primary outcomes:
measure: Non-fatal Stroke, Non-fatal Myocardial Infarction or Death Due to Vascular Causes
timeFrame: The primary outcome was measured over a median follow-up period of 3.4 years (interquartile range IQR 1.0-5.5 years).
Secondary outcomes:
Other outcomes:
Locations:
city: New York
country: United States
facility: JFK Hospital / Seton Hall University
state: New York
city: Abington
country: United States
facility: Abington Memorial Hospital
state: Pennsylvania
city: Columbia
country: United States
facility: South Carolina VA Hospital
state: South Carolina
city: Columbia
country: United States
facility: University of South Carolina
state: South Carolina
city: Gosford
country: Australia
facility: Central Coast Neuroscience Research
city: New South Wales
country: Australia
facility: Bankstown Hospital
city: New South Wales
country: Australia
facility: John Hunter Hospital
city: New South Wales
country: Australia
facility: Liverpool Hospital
city: Perth
country: Australia
facility: Royal Perth Hospital
city: Queensland
country: Australia
facility: Greenslopes Hospital
city: Queensland
country: Australia
facility: Nambour Hospital
city: South Australia
country: Australia
facility: Flinders & Griffiths
city: Tasmania
country: Australia
facility: Royal Hobart Hospital
city: Victoria
country: Australia
facility: Alfred Hospital
city: Victoria
country: Australia
facility: Beleura & Frankston Hospital
city: Victoria
country: Australia
facility: Box Hill Hospital
city: Victoria
country: Australia
facility: National Stroke Research Institute - Austin Health
city: Western Australia
country: Australia
facility: Fremantle Hospital
city: Western Australia
country: Australia
facility: Joondalup Hospital
city: Western Australia
country: Australia
facility: Sir Charles Gairdner Hospital
city: Graz
country: Austria
facility: Karl-Franzens University Graz
city: Brugge
country: Belgium
facility: Algemeen Ziekenhuis Sint-Jan Autonome Verzorgingsinstelling
city: Rio de Janeiro
country: Brazil
facility: Universidade Federal Fluminense & Universidade Federal do Rio de Janeiro
city: Tbilisi
country: Georgia
facility: Sarajishvili Institute of Neurology and Neurosurgery
city: Pokfulam
country: Hong Kong
facility: Queen Mary Hospital
city: Shatin
country: Hong Kong
facility: Prince of Wales Hospital
city: Annamalainagar
country: India
facility: Rajah Muthaiah Medical College
city: Bangalore
country: India
facility: St John's Medical College Hospital
city: Bikaner
country: India
facility: SP Medical College
city: Calicut
country: India
facility: Baby Memorial Hospital
city: Chennai
country: India
facility: KS Hospital
city: Cochin
country: India
facility: Amrita Institute of Medical Science
city: Hyderabad
country: India
facility: Care Hopstial
city: Hyderabad
country: India
facility: Mahaveer Hospital & Research Centre
city: Hyderabad
country: India
facility: Mediciti Hospital
city: Indore
country: India
facility: MGM Medical College & MY Hospital
city: Jaipur
country: India
facility: Monilek Hospital
city: Kolkata
country: India
facility: Centauri, The Albert Road Clinic
city: Lucknow
country: India
facility: CSMMU
city: Ludhiana
country: India
facility: Christian Medical College & Hospital
city: New Delhi
country: India
facility: G.B. Pant Hospital
city: New Delhi
country: India
facility: Sir Ganga Ram Hospital
city: Patiaala
country: India
facility: Sadhbavana Medical & Heart Institute
city: Perambur
country: India
facility: Railway Hospital
city: Pune
country: India
facility: Poona Hospital
city: Pune
country: India
facility: Ruby Hall Clinic
city: Trichy
country: India
facility: Neurocenter
city: Visakhapatnam
country: India
facility: Care Hospital
city: Wardha
country: India
facility: Mahatma Gandhi Institute
city: Brescia
country: Italy
facility: Spedali Civili Di Brescia
city: Busto Arsizio
country: Italy
facility: Ospedale di Circolo de Busto Arsizio
city: Macerata
country: Italy
facility: Ospedale di Macerata
city: Pavia
country: Italy
facility: IRCCS Fondazione Istituto Neurologico C Mondino
city: Perugia
country: Italy
facility: Perugia Stroke Service & Citta Della Peive
city: Perugia
country: Italy
facility: University of Perugia
city: Vittoria
country: Italy
facility: Ospedale R Guzzardi
city: Kelantan
country: Malaysia
facility: Hospital Universiti Sains Malaysia
city: Kuala Lumpur
country: Malaysia
facility: University of Malaya Medical Centre
city: Chishinau
country: Moldova, Republic of
facility: City Emergency Hospital
city: Amsterdam
country: Netherlands
facility: Slotervaartziekenhuis
city: Goes
country: Netherlands
facility: Oosterscheldeziekenhuis
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
city: Auckland
country: New Zealand
facility: Auckland Hospital
city: Hastings
country: New Zealand
facility: Hawkes Bay Hospital
city: Palmerston North
country: New Zealand
facility: Palmerston North Hospital
city: Takapuna
country: New Zealand
facility: North Shore Hospital
city: Wellington South
country: New Zealand
facility: Wellington Hospital
city: Islamabad
country: Pakistan
facility: KRL University
city: Islamabad
country: Pakistan
facility: Pakistan Institute of Medical Sciences
city: Karachi
country: Pakistan
facility: DUHS - Civil Hospital
city: Karachi
country: Pakistan
facility: DUHS - Jinnah Hospital
city: Wah Cantt
country: Pakistan
facility: POF Hospital Wah Cantt.
city: Cebu City
country: Philippines
facility: Cagayan de Oro Medical Center
city: Cebu City
country: Philippines
facility: Cebu Doctor's Hospital
city: Cebu City
country: Philippines
facility: Cebu Velez General Hospital/ Visayas Comm. Medical Center
city: Cebu City
country: Philippines
facility: Chong Hua Hospital
city: Cebu City
country: Philippines
facility: Vicente Sotto Memorial Hospital
city: East Santiago City
country: Philippines
facility: Cagayan Valley Medical Center
city: Manila
country: Philippines
facility: Jose R Reyes Memorial Medical Centre
city: Manila
country: Philippines
facility: University Santo Tomas Hospital
city: Estarreja
country: Portugal
facility: Hospital Visconde de Salreu
city: Lisboa
country: Portugal
facility: Hospital de Santa Maria
city: Oliveira de Azemeis
country: Portugal
facility: Hospital Distrital de Oliverira de Azemeis
city: Porto
country: Portugal
facility: Hospital Geral de Santo Antonio
city: Novisad
country: Serbia
facility: University of Novi Sad - Neurology & Neurosurgery
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Colombo
country: Sri Lanka
facility: National Hospital of Sri Lanka
city: Ragama
country: Sri Lanka
facility: University of Kelaniya
city: Stoke on Trent
country: United Kingdom
facility: University Hospital of North Staffordshire
state: Shaffordshire
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Barking
country: United Kingdom
facility: Redbridge Health Care
city: Barnsley
country: United Kingdom
facility: Barnsley District Hospital
city: Belfast
country: United Kingdom
facility: The Royal Victoria Hospital
city: Ceredigion
country: United Kingdom
facility: Bronglais General Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital, Edinburgh
city: Exeter
country: United Kingdom
facility: Royal Devon & Exeter Hospital
city: Glasgow
country: United Kingdom
facility: Western Infirmary
city: Huddersfield
country: United Kingdom
facility: St Luke's Hospital
city: Kent
country: United Kingdom
facility: William Harvey Hospital
city: Liverpool
country: United Kingdom
facility: University Hospital Aintree
city: Londonderry
country: United Kingdom
facility: Altnagelvin Hospital
city: Luton
country: United Kingdom
facility: Luton and Dunstable Hospital
city: Newcastle
country: United Kingdom
facility: Royal Victoria Infirmary, Newcastle
city: North Shields
country: United Kingdom
facility: North Tyneside District General Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
city: Paddington
country: United Kingdom
facility: St Mary's Paddington Hospital
city: Rotherham
country: United Kingdom
facility: Rotherham General Hospital
city: Stirling
country: United Kingdom
facility: Stirling Royal Infirmary
city: Stockport
country: United Kingdom
facility: Stepping Hill Hospital
city: Taunton
country: United Kingdom
facility: Musgrove Park Hosptial
city: Torquay
country: United Kingdom
facility: Torbay Hospital
Study officials:
affiliation: Royal Perth Hospital / University of Western Australia
name: Graeme Hankey, MBBS/MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Royal Perth Hospital
name: Ross Baker, MBBS/BMedSc
role: STUDY_DIRECTOR
affiliation: Royal Perth Hospital
name: John Eikelboom, MBBS/FRACP
role: STUDY_DIRECTOR
affiliation: The University of Queensland
name: Konrad Jamrozik, MBBS
role: STUDY_DIRECTOR
affiliation: Royal Perth Hospital
name: Frank van Bockxmeer, BSc/PhD
role: STUDY_DIRECTOR
affiliation: The University of Western Australia
name: Siobhan Hickling, BSc/MPH
role: STUDY_DIRECTOR
affiliation: Royal Perth Hospital
name: Anna Gelavis, BPharm
role: STUDY_DIRECTOR
References:
citation: Gommans J, Yi Q, Eikelboom JW, Hankey GJ, Chen C, Rodgers H; VITATOPS trial study group. The effect of homocysteine-lowering with B-vitamins on osteoporotic fractures in patients with cerebrovascular disease: substudy of VITATOPS, a randomised placebo-controlled trial. BMC Geriatr. 2013 Sep 3;13:88. doi: 10.1186/1471-2318-13-88.
citation: Hankey GJ, Ford AH, Yi Q, Eikelboom JW, Lees KR, Chen C, Xavier D, Navarro JC, Ranawaka UK, Uddin W, Ricci S, Gommans J, Schmidt R, Almeida OP, van Bockxmeer FM; VITATOPS Trial Study Group. Effect of B vitamins and lowering homocysteine on cognitive impairment in patients with previous stroke or transient ischemic attack: a prespecified secondary analysis of a randomized, placebo-controlled trial and meta-analysis. Stroke. 2013 Aug;44(8):2232-9. doi: 10.1161/STROKEAHA.113.001886. Epub 2013 Jun 13.
citation: Cavalieri M, Schmidt R, Chen C, Mok V, de Freitas GR, Song S, Yi Q, Ropele S, Grazer A, Homayoon N, Enzinger C, Loh K, Wong KS, Wong A, Xiong Y, Chang HM, Wong MC, Fazekas F, Eikelboom JW, Hankey GJ; VITATOPS Trial Study Group. B vitamins and magnetic resonance imaging-detected ischemic brain lesions in patients with recent transient ischemic attack or stroke: the VITAmins TO Prevent Stroke (VITATOPS) MRI-substudy. Stroke. 2012 Dec;43(12):3266-70. doi: 10.1161/STROKEAHA.112.665703. Epub 2012 Oct 23.
citation: Hankey GJ, Eikelboom JW, Yi Q, Lees KR, Chen C, Xavier D, Navarro JC, Ranawaka UK, Uddin W, Ricci S, Gommans J, Schmidt R; VITATOPS trial study group. Antiplatelet therapy and the effects of B vitamins in patients with previous stroke or transient ischaemic attack: a post-hoc subanalysis of VITATOPS, a randomised, placebo-controlled trial. Lancet Neurol. 2012 Jun;11(6):512-20. doi: 10.1016/S1474-4422(12)70091-1. Epub 2012 May 2.
citation: Hankey GJ, Eikelboom JW, Yi Q, Lees KR, Chen C, Xavier D, Navarro JC, Ranawaka UK, Uddin W, Ricci S, Gommans J, Schmidt R; VITAmins TO Prevent Stroke (VITATOPS) Trial Study Group. Treatment with B vitamins and incidence of cancer in patients with previous stroke or transient ischemic attack: results of a randomized placebo-controlled trial. Stroke. 2012 Jun;43(6):1572-7. doi: 10.1161/STROKEAHA.111.641613. Epub 2012 Apr 3.
citation: Almeida OP, Marsh K, Alfonso H, Flicker L, Davis TM, Hankey GJ. B-vitamins reduce the long-term risk of depression after stroke: The VITATOPS-DEP trial. Ann Neurol. 2010 Oct;68(4):503-10. doi: 10.1002/ana.22189.
citation: VITATOPS Trial Study Group. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial. Lancet Neurol. 2010 Sep;9(9):855-65. doi: 10.1016/S1474-4422(10)70187-3. Epub 2010 Aug 3.
citation: VITATOPS Trial Study Group; Hankey GJ, Algra A, Chen C, Wong MC, Cheung R, Wong L, Divjak I, Ferro J, de Freitas G, Gommans J, Groppa S, Hill M, Spence D, Lees K, Lisheng L, Navarro J, Ranawaka U, Ricci S, Schmidt R, Slivka A, Tan K, Tsiskaridze A, Uddin W, Vanhooren G, Xavier D, Armitage J, Hobbs M, Le M, Sudlow C, Wheatley K, Yi Q, Bulder M, Eikelboom JW, Hankey GJ, Ho WK, Jamrozik K, Klijn K, Koedam E, Langton P, Nijboer E, Tuch P, Pizzi J, Tang M, Antenucci M, Chew Y, Chinnery D, Cockayne C, Loh K, McMullin L, Smith F, Schmidt R, Chen C, Wong MC, de Freitas G, Hankey GJ, Loh K, Song S. VITATOPS, the VITAmins TO prevent stroke trial: rationale and design of a randomised trial of B-vitamin therapy in patients with recent transient ischaemic attack or stroke (NCT00097669) (ISRCTN74743444). Int J Stroke. 2007 May;2(2):144-50. doi: 10.1111/j.1747-4949.2007.00111.x.