A randomized clinical trial is widely regarded as the most rigorous study design to determine the efficacy of intervention because spurious causality and bias associated with other experimental designs can be avoided. The purpose of this article is to provide clinicians and clinical researchers the types of randomized clinical trials used in stroke studies and to discuss the advantages and the limitations for each type of randomized stroke clinical trials.
LachinJM, MattsJP, WeiLJ.Randomization in clinical trials: conclusions and recommendations. Controlled Clinical Trials. 1988;9:365–374.
2.
AltmanDG.Practical Statistics for Medical Research. London: Chapman & Hall; 1991.
3.
LilfordRJ, ThorntonJG, BraunholtzD.Clinical trials and rare diseases: a way out of a conundrum. BMJ. 1995;311:1621–1625.
4.
SchulzKF, GrimesDA.Sample size calculations in randomized trials: mandatory and mystical. Lancet. 2005;365:1348–1353.
5.
WeijerC, ShapiroSH, GlassKC.For and against: clinical equipoise and not the uncertainty principle is the moral underpinning of the randomized controlled trial. BMJ. 2000;321:756–758.
6.
KwonSU, ChoYJ, KooJS, . Cilostazol prevents the progression of the symptomatic intracranial arterial stenosis. Stroke. 2005;36:782–786.
7.
Pablos-MéndezA, BarrG, SheaS.Run-in periods in randomized trials. Implications for the application of results in clinical practice. JAMA. 1998;279:222–225.
8.
HatazawaJ, ShimosegawaE, OsakiY, . Long-term angiotensin-converting enzyme inhibitor perindopril therapy improves cerebral perfusion reserve in patients with previous minor stroke. Stroke. 2004;35:2117–2122.
9.
RidkerPM, CookNR, LeeIM, . A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005;352:1293–1304.
10.
Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the on-going Physicians' Health Study. N Engl J Med. 1989;321:129–135.
11.
ZelenM.A new design for randomized clinical trials. N Engl J Med. 1979;300:1242–1245.
12.
ZelenM.Randomized consent designs for clinical trials: an update. Stat Med. 1990;9:645–656.
13.
RogersH, AtkinsonC, BondS, . Randomized controlled trial of comprehensive stroke education program for patients and caregivers. Stroke. 1999;30:2585–2591.
14.
DennisM, O'RourkeS, SlatteryJ, . Evaluation of a stroke family care worker: results of a randomized controlled trial. BMJ. 1997;314:1071–1076.
15.
DonnerA, KlarN.Design and Analysis of Cluster Randomization Trials in Health Research. London: Arnold; 2000.
16.
PanellaM, MarchisioS, BarbieriA, . A cluster randomized trial to assess the impact of clinical pathways for patients with stroke: rationale and design of the clinical pathways for effective and appropriate care study [NCT00673491]. BMC Health Serv Res. 2008;8:223.
17.
DirksM, NiessenLW, HuijsmanR, . Promoting acute thrombolysis for ischemic stroke (PRACTISE). Int J Stroke. 2007;2:151–159.
The GUSTO Investigators.An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993;329:673–682.
20.
MehtaSR, BassandJP, ChrolaviciusS, . On behalf of the CURRENT OASIS 7 Steering Committee. Design and rationale of CURRENT-OASIS 7: a randomized, 2 × 2 factorial trial evaluating optimal dosing strategies for clopidogrel and aspirin in patients with ST and non-ST-elevation acute coronary syndromes managed with an early invasive strategy. Am Heart J. 2008;156:1080–1088.
21.
ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: a randomized factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet. 1995;345:669–685.
22.
Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med. 1989;321:129–135.
23.
The Canadian Cooperative Study Group. A randomized trial of aspirin and sulfinpyrazone in threatened stroke. N Engl J Med. 1978;299:53–59.
24.
GalloP, Chuang-SteinC, DragalinV, . Adaptive design in clinical drug development-an executive summary of the PhRMA Working Group (with discussions). J Biopharm Stat. 2006;16:275–283.
25.
EMEA. Reflection paper on methodological issues in confirmatory clinical trials with flexible design and analysis plan. Doc. Ref. CHMP/EWP/2459/02. Available at: http://www.emea.europa.eu/pdfs/human/ewp/245902en.pdf. AccessedDecember1, 2009.
26.
ElkindMS, SaccoRL, MacArthurRB, . The Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART): an adaptive design phase I dose-escalation study of high-dose lovastatin in acute ischemic stroke. Int J Stroke. 2008;3:210–218.
27.
ElkindMS, SaccoRL, MacarthurRB, . High-dose lovastatin for acute ischemic stroke: results of the phase I dose escalation neuroprotection with statin therapy for acute recovery trial (NeuSTART). Cerebrovasc Dis. 2009;28:266–275.
28.
O'QuigleyJ, PepeM, FisherM.Continual reassessment method: a practical design for phase I clinical trials in cancer. Biometrics. 1990;46:33–48.
29.
KramsM, LeesKR, HackeW, . ASTIN Study Investigators. Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): an adaptive dose-response study of UK-279,276 in acute ischemic stroke. Stroke. 2003;34:2543–2548.
30.
KramsM, LeesKR, BerryDA.The past is the future: innovative designs in acute stroke therapy trials. Stroke. 2005;36:1341–1347.
31.
GrieveAP, KramsM.ASTIN: a Bayesian adaptive dose-response trial in acute stroke. Clin Trials. 2005;2:340–351. Discussion 352–358, 364–378.
32.
OkuguchiT, OsanaiT, FujiwaraN, . Effect of losartan on nocturnal blood pressure in patients with stroke: comparison with angiotensin converting enzyme inhibitor. Am J Hypertens. 2002;15:998–1002.
33.
CorrS, PhillipsCJ, WalkerM.Evaluation of a pilot service designed to provide support following stroke: a randomized cross-over design study. Clin Rehabil. 2004;18:69–75.
