Clinical Trial Issues in Stroke Therapy

  • Richard C. Meibach
Part of the Advances in Neuroprotection book series (AN, volume 22)


The 1990s have been designated as the “Decade of the Brain.” In a position statement, the National Advisory Neurological Disorders and Stroke Council (1990) stated that during this period we will see “The prevention of 80% of all strokes and protection of the brain during the acute stroke.” To accomplish this task new therapies must be developed. The safety and efficacy of any new agent must be demonstrated in adequate and well-controlled trials. The fact that there are no effective agents in the area of stroke treatment prevents us from having a standard to which new agents can be compared. Without a baseline it becomes difficult to select the proper dosage, determine the maximum treatment duration, and choose the proper measurements in order to assess the efficacy of a new agent. There have been numerous agents tested over the past decade. Unfortunately there is still no consensus among stroke investigators as to the ideal protocol design. A critical review of past studies can help determine strategies for a successful development program of future drugs. It is hoped that this review can encourage the development of adequate and well-controlled protocols that will fulfill the U.S. Food and Drug Administration’s (FDA’s) requirements.


Acute Stroke Acute Ischemic Stroke Stroke Trial Stroke Therapy Clinical Trial Methodology 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abe K, Kogure K, Watanabe T (1988): Prevention of ischemic and postischemic brain edema by a novel calcium antagonist (PN 200–110). J Cereb Blood Flow Metab 8: 436–439CrossRefGoogle Scholar
  2. Abramson NS, Meisel A, Safar P (1986): Deferred consent: A new approach for resuscitation research on comatose patients JAMA 255: 2466–2471PubMedGoogle Scholar
  3. Adams HP Jr, Olinger CP, Barsan WG, Butler MJ, Graff-Radford NR, Brott TG, Biller J, Damasio H, Tomsick T, Goldberg M, Spilker JA, Berlinger E, Dambrosia J, Biros M, Hollern R (1986): A dose-escalation study of large doses of naloxone for treatment of patients with acute cerebral ischemia. Stroke 17: 404–409PubMedGoogle Scholar
  4. Adams RJ, Meador KJ, Sethi KD, Grotta JC, Thomson DS (1987): Graded neurologic scale for use in acute hemispheric stroke treatment protocols. Stroke 18: 665–669PubMedGoogle Scholar
  5. Adams RJ, Nichols FT, Thompsom WO (1989): Neurological assessment in acute stroke. Issues in the use of rating scales. In: Clinical Trial Methodology in Stroke, Amery WK, Bousser M-G, Clifford Rose F, eds. London: Bailliere TindallGoogle Scholar
  6. Barer DH, Ebrahim SB, Mitchell JRA (1988): The pragmatic approach to stroke trial design: Stroke register, pilot trial, assessment of neurological then functional outcome. Neuroepidemiology 7: 1–12PubMedGoogle Scholar
  7. Barsan WG, Brott TG, Olinger CP, Adams HP Jr, Haley EC Jr, Levy DE (1988): Identification and entry of the patient with acute cerebral infarction. Ann Emerg Med 17: 1192–1195PubMedGoogle Scholar
  8. Barsan WG, Brott TG, Olinger CP, Marler JR (1989): Early treatment for acute ischemic stroke. Ann Intern Med 111: 449–451PubMedGoogle Scholar
  9. Bayer AJ, Pathy MSJ, Newcombe R (1987): Double-blind randomized trial of intravenous glycerol in acute stroke. Lancet i:405–407Google Scholar
  10. Bielenberg GW, Burkhardt M (1990): 5–Hydroxytryptamine, A agonists. A new therapeutic principle for stroke treatment. Stroke 21 (Suppl IV):IV161–IV163PubMedGoogle Scholar
  11. Biller J, Love BB, Marsh EE III, Jone MP, Knepper LE, Jiang D, Adams HP Jr, Gordon DL (1990) Spontaneous improvement after acute ischemic stroke: A pilot study. Stroke 21: 1008–1012PubMedGoogle Scholar
  12. Biller J, Massey EW, Marler JR, Adams HP, Davis JN, Bruno A, Henriksen RA, Linhardt RJ, Goldstein LB, Alberts M, Kisker CT, Toffol GJ, Greenberg CS, Ganwart KJ, Bertels C, Beck DW, Walker M, Magnani HN (1989): A dose escalation study of ORG 10172 (low molecular weight heparinoid) in stroke. Neurology 39: 262–265PubMedGoogle Scholar
  13. Bogousslaysky J, Regli F, Zumstein V, Kobberling W (1990): Double-blind study of nimodipine in non-severe stroke. Eur Neurol 30: 23–26Google Scholar
  14. Britton M, Roden A (1986): Progression of stroke after arrival at hospital. Stroke 16: 629–632Google Scholar
  15. Brott T, Adams HP Jr, Olinger CP, Marler JR, Barsan WG, Biller J, Spilker J, Holleran R, Eberle R, Hertzberg V, Rorick M, Moomaw CJ, Walker M (1989): Measurements of acute cerebral infarction: A clinical examination scale. Stroke 20: 864–870PubMedGoogle Scholar
  16. Brott TG, Haley EC, Levy DE, Barsan WG, Reed RL, Olinger CP, Marler JR (1988): Tissue plasminogen activator (tPA) as very early therapy for cerebral infarction. Stroke 19: 133Google Scholar
  17. Brott TG, Haley EC, Levy DE, Barsan W, Sheppard G, Broderick J, Reed R, Marler J (1990): Safety and potential efficacy of tissue plasminogen activator (tPA) for stroke. Stroke 21: 27Google Scholar
  18. Buchan AM, Xue D, Slivka A (1990): MK-801 reduces the volume of neocortical infarction but also increases regional cerebral blood flow. Stroke 21: 9Google Scholar
  19. Capildeo R, Haberman S, Rose FC (1982): Stroke trials: The facts. Advan Stroke Ther 16: 413–416Google Scholar
  20. Candelise L (1989): Clinical trial methodology in stroke. Multicentre studies: Keep the protocol simple. In: Clinical Trial Methodology in Stroke, Amery WK, Bousser MG, Clifford Rose F, eds, London: Bailliere TindallGoogle Scholar
  21. Cooper A (1836): Some experiments and observations on tying the carotid and vertebral arteries. Guys Hosp Rep 1: 458–475Google Scholar
  22. Cote R, Battista RN, Wolfson M, Hachinski VC (1988): Stroke assessment scales: Guidelines for development, validation, and reliability assessment. Can J Neurol Sci 15: 261–265PubMedGoogle Scholar
  23. Cote R, Battista RN, Wolfson M, Boucher J, Adam J, Hachinski VC (1989): The Canadian Neurological Scale: Validation and reliability assessment. Neurology 39: 638–643PubMedGoogle Scholar
  24. Cote R, Hachinski VC, Shurvell BL, Norris JW, Wolfson C (1986): The CanadianGoogle Scholar
  25. Neurological Scale: A preliminary study in acute stroke. Stroke 17: 731–737Google Scholar
  26. Czionkowska A, Cyrta B (1988): Effects of naloxone on acute stroke. Pharmacopsychiatry 21: 98–100Google Scholar
  27. Davalos A, Cendra E, Teruel J, Martinez M, Genis D (1990): Deteriorating ischemic stroke: Risk factors and prognosis. Neurology 40: 1865–1869PubMedGoogle Scholar
  28. del Zuppo GJ (1990): An open, multicenter trial of recombinant tissue plasminogen activator in acute stroke. A progress report. Stroke 21 (Suppl IV):IV174–IV175Google Scholar
  29. Duncan PW, Propst M, Nelson SG (1983): Reliability of the Fugl-Meyer assessment of sensorimotor recovery following cerebrovascular accident. Phys Ther 63: 1606–1610PubMedGoogle Scholar
  30. Frei A, Cottier C, Wunderlich P (1987): Glycerol and dextran combined in the therapy of acute stroke. A placebo-controlled, double-blind trial with a planned interim analysis. Stroke 18: 373–379PubMedGoogle Scholar
  31. Fugl-Meyer AR, Jaasko L, Leyman I, Olsson S, Steglind S (1975): The post-stroke hemiplegic patient. I. A method for evaluation of physical performance. Scand J Rehabil Med 14: 27–32Google Scholar
  32. Gelmers HJ (1984): The effects of nimodipine on the clinical course of patients with acute ischemic stroke. Acta Neurol Scand 69: 232–239PubMedGoogle Scholar
  33. Gelmers HJ, Hennerici M (1990): Effect of nimodipine on acute ischemic stroke. Pooled results from five randomized trials. Stroke 21 (Suppl IV):IV81–IV84Google Scholar
  34. Gelmers HJ, Gorter K, de Weerdt CJ, Wiezer HJA (1988): A controlled trial of nimodipine in acute ischemic stroke. N Engl J Med 318: 203–207PubMedPubMedCentralGoogle Scholar
  35. Giraldi C, Masi MC, Manetti M, Carabelli E, Martini A (1990): A pilot study with monosialoganglioside GM1 on acute cerebral ischemia. Inst Clin Neurol Pisa Univ 214–221Google Scholar
  36. Goldstein LB, Bertels C, Davis JN (1989): Interrater reliability of the NIH stroke scale. Arch Neurol 46: 660–662PubMedGoogle Scholar
  37. Gowland CA (1990): Staging motor impairment after stroke. Stroke 21 (Suppl II):II19–1I21Google Scholar
  38. Grotta JC, Rosenbaum D, Zabramski J, Picone C, Pettigrew LC, Marier J, Ellis D, Bratina P, Lopez L, Spetzler R (1988): Pilot study of nicardipine (NC) for acute stroke (abstract). Neurology 38 (Suppl 1): 109Google Scholar
  39. Grotta JC, Picone CM, Yao L (1990): CGS 19755 reduces calcium-calmodulin binding after cerebral ischemia. Stroke 21: 7Google Scholar
  40. Hachinski V (1990): Classification of stroke for clinical trials. Stroke 21 (Suppl II): I127–1129Google Scholar
  41. Hsu CY, Faught RE Jr, Furlan AJ, Coull BM, Huang DC, Hogan EL, Linet OI, Yatsu FM (1987): Intravenous prostacyclin in acute nonhemorrhagic stroke: A placebo-controlled double-blind trial. Stroke 18: 352–358PubMedGoogle Scholar
  42. Hsu CY, Norris JW, Hogan EL (1988): Pentoxifylline in acute nonhemorrhagic stroke. A randomized, placebo-controlled, double-blind trial. Stroke 19: 716–722PubMedGoogle Scholar
  43. Hulser PJ, Bernhart H, Marbach C, Kornhuber HH (1988): Treatment with an i.v. calcium overload blocker (flunarizine) in acute stroke. A pilot study. Eur Arch Psychiatr Neurol Sci 237: 253–257Google Scholar
  44. Hulser PJ, Kornhuber AW, Kornhuber HH (1990): Treatment of Acute Stroke with Calcium Antagonists, Eur Neurol 30 (Suppl 2): 25–38Google Scholar
  45. Kramer G, Tettenborn B, Rothacker G, Hacke W, Busse O, Hornig CR, Aichner F, Ladurner G (1990): Nimodipine German-Austrian stroke trial (abstract). Neurology 40 (Suppl I): 415–416Google Scholar
  46. LaRue LJ, Alter M, Traven ND (1988): Acute stroke therapy trials: Problems in patient accrual. Stroke 19: 950–954PubMedGoogle Scholar
  47. Limburg M, Hijdra A (1990): Flunarizine in acute ischemic stroke: A pilot study. Eur Neurol 30: 121–122PubMedPubMedCentralGoogle Scholar
  48. Lin B, Dietrich D, Busto R, Ginsberg MD (1990): (s)-Emopamil protects against global ischemic injury in rats. Stroke 21: 1734–1739PubMedPubMedCentralGoogle Scholar
  49. Loewen SC, Anderson BA (1988): Reliability of the modified motor assessment scale and the Barthel index. Phys Ther 68: 1077–1081PubMedGoogle Scholar
  50. Mahoney FI, Barthel DW (1965): Functional evaluation. The Barthel index. Md State Med J 14: 61–65PubMedGoogle Scholar
  51. Martin JF, Handy N, Nicholl J, Lewtas N, Bergvall U, Owen P, Syder D, Holroyd M (1985): Double-blind controlled trial of prostacyclin in cerebral infarction. Stroke 16: 386–390PubMedGoogle Scholar
  52. Martinez-Vila E, Guillen F, Villanueva JA, Matias-Guiru J, Bigorra J, Gil P, Carbonell A, Martinez-Lage JM (1990): Placebo-controlled trial of nimodipine in the treatment of acute ischemic cerebral infarction. Stroke 21: 1023–1028PubMedPubMedCentralGoogle Scholar
  53. Massey EW, Biller J, Davis JN, Adams HP Jr, Marler JR, Goldstein LB, Alberts M, Bruno A (1990): Large-dose infusions of heparinoid ORG 10172 in ischemic stroke. Stroke 21: 1289–1292PubMedGoogle Scholar
  54. Mathew NT, Meyer JS, Rivera VH, Charney JZ, Hartmann A (1972): Double-blind evaluation of glycerol treatment in acute cerebral infarction. Lancet ii: 1327–1329Google Scholar
  55. Mohr JP, Dijanni M, Muschett JL, Riccio RV, GH Besselaar Associates, Nimodipine Study Group (1989): Nimodipine in acute ischemic stroke. Ann Neurol 26: 124Google Scholar
  56. Molinari GF (1988): Why model strokes? Stroke 19: 1195–1197PubMedGoogle Scholar
  57. Nakayama H, Ginsberg MD, Dietrich, WD (1988): (s)-Emopamil, a novel calcium channel blocker and serotonin SZ antagonist, markedly reduces infarct size following middle cerebral artery occlusion in the rat. Neurology 38: 1667–1673PubMedPubMedCentralGoogle Scholar
  58. National Advisory Neurological Disorders and Stroke Council (1990): Implementation plan for the decade of the brain. Executive Summary. Neurology 40: 1483–1486Google Scholar
  59. Norris JW (1983) Comment on “Study design of stroke treatments” (letter). Stroke 13: 527–528Google Scholar
  60. Oczkowski WJ, Hachinski VC, Bogousslaysky J, Barnett HJM, Carruthers SG (1989): A double-blind, randomized trial of PY108–068 in acute ischemic cerebral infarction. Stroke 20: 604–608PubMedGoogle Scholar
  61. Olesen J, Simonsen K, Norgaard B (1988) Reproducibility and utility of a simple neurological scoring system for stroke patients (Copenhagen stroke scale). J Neurol Rehab 2: 59–63Google Scholar
  62. Olinger CP, Adams HP Jr, Brott TG, Biller J, Barsan WG, Toffol GJ, Eberle RW, Marler JR (1990): High-dose intravenous naloxone for the treatment of acute ischemic stroke. Stroke 21: 721–725PubMedGoogle Scholar
  63. Orgogozo JM (1989): Evaluation of treatments in ischemic-stroke patients. In: Clinical Trial Methodology in Stroke, Amery WK, Bousser M-G, Clifford Rose F, eds, London: Bailliere TindallGoogle Scholar
  64. Orgogozo JM, Capildeo R, Anagnostou CN (1983): Mise au point d’un score neurologigue pour l’évaluation cliniques des infarctus sylviens. Nouv Presse Med 12: 3039–3044Google Scholar
  65. Orgogozo JM, Dartigues JF (1986): Clinical trials in acute brain infarction. The question of assessment criteria. In: Acute Brain Ischemia, Battistini N et al., eds. New York: Raven PressGoogle Scholar
  66. Oxbury JM, Greenhall RCD, Grainger KMR (1975): Predicting the outcome of stroke: Acute stage after cerebral infarction. Br Med J 3: 125–127PubMedPubMedCentralGoogle Scholar
  67. Paci A, Ottaviano P, Trenta A, Iannone G, De Santis L, Lancia G, Moschini E, Carosi M, Amigoni S, Caresia L (1989): Nimodipine in acute ischemic stroke: a double-blind controlled study. Acta Neurol Scand 80: 282–286PubMedPubMedCentralGoogle Scholar
  68. Parkinson Study Group (1989): Effect of deprenyl (selegiline) on the progression of disability in early Parkinson’s disease. N Engl J Med 321 (20): 1364–1371Google Scholar
  69. Patten BM, Mendell J, Bruun B, Curtin W, Carter S (1972): Double-blind study of the effects of dexamethasone on acute stroke. Neurology 22: 377–383PubMedGoogle Scholar
  70. Pulsinelli WA, Buchan A (1989): The utility of animal ischemia models in predicting pharmacotherapeutic response in the clinical setting. In: Cerebrovascular Diseases, Ginsberg MD, Dietrich WD, eds. New York: Raven PressGoogle Scholar
  71. Rosenbaum DM, Grotta JC, Yatsu FM, Picone CM, Pettigrew LC, Bratina P, Zabramski J, Spetzler R, Lopez L, Marler J, Ellis D (1990): Pilot study of nicardipine for acute ischemic stroke. Angiology-T J Vasc Dis 1017–1022Google Scholar
  72. Rosenbaum DM, Zabramski J, Frey J, Yatsu F, Marler J, Spetzler R, Grotta J (1991): Early treatment of ischemic stroke with a calcium antagonist. Stroke 22: 437–441PubMedGoogle Scholar
  73. Sauter A, Rudin M (1990): Calcium antagonists for reduction of brain damage in stroke. J Cardiovasc Pharmacol 15 (Suppl 1): S43–S47PubMedGoogle Scholar
  74. Spence JD, Donner A (1982): Problems in design of stroke treatment trials. Stroke 13: 94–99PubMedGoogle Scholar
  75. Steiner TJ, Clifford Rose F (1986a): Randomized double-blind placebo-controlled clinical trial of naftidrofuryl in hemiparetic CT-proven acute cerebral hemisphere infarction. R Soc Med Int Congr Symp Ser 99: 85–98Google Scholar
  76. Steiner TJ, Clifford Rose F (1986b): Towards a model stroke trial. The single-centre naftidrofuryl study. Neuroepidemiology 5: 121–147PubMedGoogle Scholar
  77. Sterman AB, Furlan AJ, Pessin P, Kase C, Caplan L, Williams G (1987): Acute stroke therapy trials: An introduction to recurring design issues. Stroke 18: 524–527PubMedGoogle Scholar
  78. Sundt TM Jr, Grant WC, Garcia JH (1969): Restoration of middle cerebral artery flow in experimental infarction. J Neurosurg 31: 311–321PubMedGoogle Scholar
  79. Tmerding BL, Barsan WG, Hedges JR, Brott TG, VanLigten PF, Spilker JA, Olinger CP (1989): Stroke patient evaluation in the emergency department before pharmacologic therapy. Am J Emerg Med 7:11–15 Google Scholar
  80. TRUST Study Group (1990): Randomised, double-blind, placebo controlled trial of nimodipine in acute stroke. Lancet 336: 1205–1209Google Scholar
  81. Tuthill JE, Pozen TJ, Kennedy FB (1969): A neurologic grading system for acute stroke. Am Heart J 78: 53–57PubMedGoogle Scholar
  82. Uematsu D, Araki N, Greenberg JH, Sladky J, Reivich M (1991): Combined therapy with MK-801 and nimodipine for protection of ischemic brain damage. Neurology 41: 88–94PubMedGoogle Scholar
  83. Walker AE, Robins M, Weinfeld FD (1981): The national survey of stroke. 3. Clinical findings. Stroke 12: 113–131Google Scholar
  84. Whisnant JP, Basford JR, Bernstein EF, Cooper ES, Dyken ML, Easton D, Little JR, Marler JR, Millikaan CH, Petito CK, Price TR, Raichle ME, Robertson JT, Thiele B, Walker MD, Zimmerman RA (1990): Classification of cerebrovascular diseases III. Stroke 21: 637–676Google Scholar
  85. Wiebers DO, Adams Jr HP, Whisnant JP (1990): Animal models of stroke: Are they relevant to human disease? Stroke 21: 1–3Google Scholar
  86. Wood-Dauphinee SL, Ivan Williams J, Shapiro SH (1990): Examining outcome measures in a clinical study of stroke. Stroke 21: 731–739PubMedGoogle Scholar
  87. Xue D, Bruederlin B, Heinicke E, Li H, Slivka A, Buchan A (1990): U74006U reduces neocortical infarction but does not attenuate selective hippocampal CA1 neurons. Stroke 21: 24Google Scholar
  88. Yatsu FM, Becker C, McLeroy KR, Coull B, Feibel J, Howard G, Toole JF, Walker MD (1986): Community hospital-based stroke programs: North Carolina, Oregon, and New York. I. Goals, objectives, and data collection procedures. Stroke 17: 276–284PubMedGoogle Scholar
  89. Zivin JA, Grotta JC (1990): Animal stroke models: They are relevant to human disease. Stroke 21: 981–983Google Scholar

Copyright information

© Birkhäuser Boston 1992

Authors and Affiliations

  • Richard C. Meibach

There are no affiliations available

Personalised recommendations