Skip to main content

Advertisement

SpringerLink
Log in

Lessons Learned from Phase II and Phase III Trials Investigating Therapeutic Agents for Cerebral Ischemia Associated with Aneurysmal Subarachnoid Hemorrhage

  • Review Article
  • Published:
Neurocritical Care Aims and scope Submit manuscript

Abstract

One of the challenges in bringing new therapeutic agents (since nimodipine) in for the treatment of cerebral ischemia associated with aneurysmal subarachnoid hemorrhage (aSAH) is the incongruence in therapeutic benefit observed between phase II and subsequent phase III clinical trials. Therefore, identifying areas for improvement in the methodology and interpretation of results is necessary to increase the value of phase II trials. We performed a systematic review of phase II trials that continued into phase III trials, evaluating a therapeutic agent for the treatment of cerebral ischemia associated with aSAH. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines for systematic reviews, and review was based on a peer-reviewed protocol (International Prospective Register of Systematic Reviews no. 222965). A total of nine phase III trials involving 7,088 patients were performed based on eight phase II trials involving 1558 patients. The following therapeutic agents were evaluated in the selected phase II and phase III trials: intravenous tirilazad, intravenous nicardipine, intravenous clazosentan, intravenous magnesium, oral statins, and intraventricular nimodipine. Shortcomings in several design elements of the phase II aSAH trials were identified that may explain the incongruence between phase II and phase III trial results. We suggest the consideration of the following strategies to improve phase II design: increased focus on the selection of surrogate markers of efficacy, selection of the optimal dose and timing of intervention, adjustment for exaggerated estimate of treatment effect in sample size calculations, use of prespecified go/no-go criteria using futility design, use of multicenter design, enrichment of the study population, use of concurrent control or placebo group, and use of innovative trial designs such as seamless phase II to III design. Modifying the design of phase II trials on the basis of lessons learned from previous phase II and phase III trial combinations is necessary to plan more effective phase III trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Connolly ES Jr, Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke. 2012;43:1711–37.

    Article  PubMed  Google Scholar 

  2. Macdonald RL, Higashida RT, Keller E, et al. Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol. 2011;10:618–25.

    Article  CAS  PubMed  Google Scholar 

  3. Dorhout Mees SM, Algra A, Vandertop WP, et al. Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial. Lancet. 2012;380:44–9.

    Article  PubMed  Google Scholar 

  4. Wason JMS, Robertson DS. Controlling type I error rates in multi-arm clinical trials: A case for the false discovery rate. Pharm Stat. 2021;20:109–16.

    Article  PubMed  Google Scholar 

  5. 22 case studies where phase 2 and phase 3 trials had divergent results. 2017. (Accessed January 19, 2020, at https://www.fda.gov/media/102332/download.)

  6. Hall ED, Travis MA. Effects of the nonglucocorticoid 21-aminosteroid U74006F on acute cerebral hypoperfusion following experimental subarachnoid hemorrhage. Exp Neurol. 1988;102:244–8.

    Article  CAS  PubMed  Google Scholar 

  7. Haley EC Jr, Kassell NF, Alves WM, Weir BK, Hansen CA. Phase II trial of tirilazad in aneurysmal subarachnoid haemorrhage. A report of the Cooperative Aneurysm Study. J Neurosurg. 1995;82:786–90.

    Article  PubMed  Google Scholar 

  8. Haley EC Jr, Kassell NF, Apperson-Hansen C, Maile MH, Alves WM. A randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in North America. J Neurosurg. 1997;86:467–74.

    Article  CAS  PubMed  Google Scholar 

  9. Kassell NF, Haley EC Jr, Apperson-Hansen C, Alves WM. Randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in Europe, Australia, and New Zealand. J Neurosurg. 1996;84:221–8.

    Article  CAS  PubMed  Google Scholar 

  10. Fleishaker JC, Hulst LK, Peters GR. The effect of phenytoin on the pharmacokinetics of tirilazad mesylate in healthy male volunteers. Clin Pharmacol Ther. 1994;56:389–97.

    Article  CAS  PubMed  Google Scholar 

  11. Fleishaker JC, Fiedler-Kelly J, Grasela TH. Population pharmacokinetics of tirilazad: effects of weight, gender, concomitant phenytoin, and subarachnoid hemorrhage. Pharm Res. 1999;16:575–83.

    Article  CAS  PubMed  Google Scholar 

  12. Hulst LK, Fleishaker JC, Peters GR, Harry JD, Wright DM, Ward P. Effect of age and gender on tirilazad pharmacokinetics in humans. Clin Pharmacol Ther. 1994;55:378–84.

    Article  CAS  PubMed  Google Scholar 

  13. Clinical drug interaction studies—Cytochrome P450 enzyme- and transporter-mediated drug interactions, guidance for industry. Food and Drug Administration, 2020. (Accessed September 20, 2021, at https://www.fda.gov/media/134581/download.)

  14. Lanzino G, Kassell NF, Dorsch NW, et al. Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid haemorrhage. Part I. A cooperative study in Europe, Australia, New Zealand, and South Africa. J Neurosurg. 1999;90:1011–7.

    Article  CAS  PubMed  Google Scholar 

  15. Lanzino G, Kassell NF. Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid haemorrhage. Part II. A cooperative study in North America. J Neurosurg. 1999;90:1018–24.

    Article  CAS  PubMed  Google Scholar 

  16. Brenner A, Arribas M, Cuzick J, et al. Outcome measures in clinical trials of treatments for acute severe haemorrhage. Trials. 2018;19:533.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Weiss NS. All-cause mortality as an outcome in epidemiologic studies: proceed with caution. Eur J Epidemiol. 2014;29:147–9.

    Article  PubMed  Google Scholar 

  18. Pace A, Mitchell S, Casselden E, et al. A subarachnoid haemorrhage-specific outcome tool. Brain. 2018;141:1111–21.

    Article  PubMed  Google Scholar 

  19. Flamm ES, Adams HP Jr, Beck DW, et al. Dose-escalation study of intravenous nicardipine in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg. 1988;68:393–400.

    Article  CAS  PubMed  Google Scholar 

  20. Haley EC Jr, Kassell NF, Torner JC, Truskowski LL, Germanson TP. A randomized trial of two doses of nicardipine in aneurysmal subarachnoid haemorrhage. A report of the Cooperative Aneurysm Study. J Neurosurg. 1994;80:788–96.

    Article  PubMed  Google Scholar 

  21. Haley EC Jr, Kassell NF, Torner JC. A randomized controlled trial of high-dose intravenous nicardipine in aneurysmal subarachnoid haemorrhage. A report of the cooperative aneurysm study. J Neurosurg. 1993;78:537–47.

    Article  PubMed  Google Scholar 

  22. Haley EC Jr, Kassell NF, Torner JC. A randomized trial of nicardipine in subarachnoid hemorrhage: angiographic and transcranial Doppler ultrasound results. A report of the Cooperative Aneurysm Study. J Neurosurg. 1993;78:548–53.

    Article  PubMed  Google Scholar 

  23. Current good manufacturing practice for phase 1 investigational drugs. 2008. (Accessed September 20, 2021, at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/current-good-manufacturing-practice-phase-1-investigational-drugs.)

  24. Macdonald RL, Kassell NF, Mayer S, et al. Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke. 2008;39:3015–21.

    Article  CAS  PubMed  Google Scholar 

  25. Macdonald RL, Higashida RT, Keller E, et al. Preventing vasospasm improves outcome after aneurysmal subarachnoid hemorrhage: rationale and design of CONSCIOUS-2 and CONSCIOUS-3 trials. Neurocrit Care. 2010;13:416–24.

    Article  PubMed  Google Scholar 

  26. Ayling OGS, Ibrahim GM, Alotaibi NM, Gooderham PA, Macdonald RL. Anemia after aneurysmal subarachnoid hemorrhage is associated with poor putcome and death. Stroke. 2018;49:1859–65.

    Article  PubMed  Google Scholar 

  27. Porchet F, Chiolero R, de Tribolet N. Hypotensive effect of nimodipine during treatment for aneurysmal subarachnoid haemorrhage. Acta Neurochir (Wien). 1995;137:62–9.

    Article  CAS  Google Scholar 

  28. Muroi C, Keller M, Pangalu A, Fortunati M, Yonekawa Y, Keller E. Neurogenic pulmonary edema in patients with subarachnoid hemorrhage. J Neurosurg Anesthesiol. 2008;20:188–92.

    Article  PubMed  Google Scholar 

  29. Ram Z, Sadeh M, Shacked I, Sahar A, Hadani M. Magnesium sulfate reverses experimental delayed cerebral vasospasm after subarachnoid hemorrhage in rats. Stroke. 1991;22:922–7.

    Article  CAS  PubMed  Google Scholar 

  30. van den Bergh WM, Zuur JK, Kamerling NA, et al. Role of magnesium in the reduction of ischemic depolarization and lesion volume after experimental subarachnoid hemorrhage. J Neurosurg. 2002;97:416–22.

    Article  PubMed  Google Scholar 

  31. van den Bergh WM, Algra A, van Kooten F, et al. Magnesium sulfate in aneurysmal subarachnoid hemorrhage: a randomized controlled trial. Stroke. 2005;36:1011–5.

    Article  PubMed  Google Scholar 

  32. van den Bergh WM, Albrecht KW, Berkelbach van der Sprenkel JW, Rinkel GJ. Magnesium therapy after aneurysmal subarachnoid haemorrhage a dose-finding study for long term treatment. Acta Neurochir (Wien) 2003;145:195–9; discussion 9.

  33. Leijenaar JF, Dorhout Mees SM, Algra A, van den Bergh WM, Rinkel GJ, Group M-IS. Effect of magnesium treatment and glucose levels on delayed cerebral ischemia in patients with subarachnoid hemorrhage: a substudy of the Magnesium in Aneurysmal Subarachnoid Haemorrhage trial (MASH-II). Int J Stroke 2015;10 Suppl A100:108–12.

  34. Wong GK, Chan MT, Boet R, Poon WS, Gin T. Intravenous magnesium sulfate after aneurysmal subarachnoid hemorrhage: a prospective randomized pilot study. J Neurosurg Anesthesiol. 2006;18:142–8.

    Article  PubMed  Google Scholar 

  35. Veyna RS, Seyfried D, Burke DG, et al. Magnesium sulfate therapy after aneurysmal subarachnoid hemorrhage. J Neurosurg. 2002;96:510–4.

    Article  CAS  PubMed  Google Scholar 

  36. Wong GK, Poon WS, Chan MT, et al. Intravenous magnesium sulphate for aneurysmal subarachnoid hemorrhage (IMASH): a randomized, double-blinded, placebo-controlled, multicenter phase III trial. Stroke. 2010;41:921–6.

    Article  CAS  PubMed  Google Scholar 

  37. Akdemir H, Kulakszoglu EO, Tucer B, Menkü A, Postalc L, Günald Ö. Magnesium sulfate therapy for cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Neurosurg Q. 2009;19:35–9.

    Article  Google Scholar 

  38. Muroi C, Terzic A, Fortunati M, Yonekawa Y, Keller E. Magnesium sulfate in the management of patients with aneurysmal subarachnoid hemorrhage: a randomized, placebo-controlled, dose-adapted trial. Surg Neurol. 2008;69:33–9.

    Article  PubMed  Google Scholar 

  39. Bulsara KR, Coates JR, Agrawal VK, et al. Effect of combined simvastatin and cyclosporine compared with simvastatin alone on cerebral vasospasm after subarachnoid hemorrhage in a canine model. Neurosurg Focus. 2006;21:E11.

    Article  PubMed  Google Scholar 

  40. Tseng MY, Czosnyka M, Richards H, Pickard JD, Kirkpatrick PJ. Effects of acute treatment with pravastatin on cerebral vasospasm, autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid hemorrhage: a phase II randomized placebo-controlled trial. Stroke. 2005;36:1627–32.

    Article  CAS  PubMed  Google Scholar 

  41. Kirkpatrick PJ, Turner CL, Smith C, Hutchinson PJ, Murray GD, Collaborators S. Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial. Lancet Neurol. 2014;13:666–75.

    Article  CAS  PubMed  Google Scholar 

  42. Lennernas H, Fager G. Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Similarities and differences Clin Pharmacokinet. 1997;32:403–25.

    Article  CAS  PubMed  Google Scholar 

  43. Chou SH, Smith EE, Badjatia N, et al. A randomized, double-blind, placebo-controlled pilot study of simvastatin in aneurysmal subarachnoid hemorrhage. Stroke. 2008;39:2891–3.

    Article  CAS  PubMed  Google Scholar 

  44. Garg K, Sinha S, Kale SS, et al. Role of simvastatin in prevention of vasospasm and improving functional outcome after aneurysmal sub-arachnoid hemorrhage: a prospective, randomized, double-blind, placebo-controlled pilot trial. Br J Neurosurg. 2013;27:181–6.

    Article  CAS  PubMed  Google Scholar 

  45. Vergouwen MD, de Haan RJ, Vermeulen M, Roos YB. Effect of statin treatment on vasospasm, delayed cerebral ischemia, and functional outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis update. Stroke. 2010;41:e47-52.

    Article  CAS  PubMed  Google Scholar 

  46. Hanggi D, Etminan N, Macdonald RL, et al. NEWTON: Nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage. Neurocrit Care. 2015;23:274–84.

    Article  PubMed  Google Scholar 

  47. Carlson AP, Hanggi D, Wong GK, et al. Single-dose intraventricular nimodipine microparticles versus oral nimodipine for aneurysmal subarachnoid hemorrhage. Stroke. 2020;51:1142–9.

    Article  CAS  PubMed  Google Scholar 

  48. Hanggi D, Etminan N, Aldrich F, et al. Randomized, Open-Label, Phase 1/2a Study to Determine the Maximum Tolerated Dose of Intraventricular Sustained Release Nimodipine for Subarachnoid Hemorrhage (NEWTON [Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage]). Stroke. 2017;48:145–51.

    Article  PubMed  Google Scholar 

  49. Shen J, Pan JW, Fan ZX, Xiong XX, Zhan RY. Dissociation of vasospasm-related morbidity and outcomes in patients with aneurysmal subarachnoid hemorrhage treated with clazosentan: a meta-analysis of randomized controlled trials. J Neurosurg. 2013;119:180–9.

    Article  PubMed  Google Scholar 

  50. Vergouwen MD, Ilodigwe D, Macdonald RL. Cerebral infarction after subarachnoid hemorrhage contributes to poor outcome by vasospasm-dependent and -independent effects. Stroke. 2011;42:924–9.

    Article  PubMed  Google Scholar 

  51. Dhar R, Scalfani MT, Blackburn S, Zazulia AR, Videen T, Diringer M. Relationship between angiographic vasospasm and regional hypoperfusion in aneurysmal subarachnoid hemorrhage. Stroke. 2012;43:1788–94.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Budohoski KP, Czosnyka M, Smielewski P, et al. Impairment of cerebral autoregulation predicts delayed cerebral ischemia after subarachnoid hemorrhage: a prospective observational study. Stroke. 2012;43:3230–7.

    Article  PubMed  Google Scholar 

  53. Otite F, Mink S, Tan CO, et al. Impaired cerebral autoregulation is associated with vasospasm and delayed cerebral ischemia in subarachnoid hemorrhage. Stroke. 2014;45:677–82.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Lucke-Wold BP, Logsdon AF, Manoranjan B, et al. Aneurysmal subarachnoid hemorrhage and neuroinflammation: A comprehensive review. Int J Mol Sci. 2016;17:497.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Okada T, Suzuki H. Mechanisms of neuroinflammation and inflammatory mediators involved in brain injury following subarachnoid hemorrhage. Histol Histopathol. 2020;35:623–36.

    CAS  PubMed  Google Scholar 

  56. Pu T, Zou W, Feng W, et al. Persistent malfunction of glymphatic and meningeal lymphatic drainage in a mouse model of subarachnoid hemorrhage. Exp Neurobiol. 2019;28:104–18.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Claassen J, Carhuapoma JR, Kreiter KT, Du EY, Connolly ES, Mayer SA. Global cerebral edema after subarachnoid hemorrhage: frequency, predictors, and impact on outcome. Stroke. 2002;33:1225–32.

    Article  PubMed  Google Scholar 

  58. Hayman EG, Wessell A, Gerzanich V, Sheth KN, Simard JM. Mechanisms of global cerebral edema formation in aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2017;26:301–10.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Korn EL, Albert PS, McShane LM. Assessing surrogates as trial endpoints using mixed models. Stat Med. 2005;24:163–82.

    Article  PubMed  Google Scholar 

  60. Rubinstein L, Crowley J, Ivy P, Leblanc M, Sargent D. Randomized phase II designs. Clin Cancer Res. 2009;15:1883–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Dhani N, Tu D, Sargent DJ, Seymour L, Moore MJ. Alternate endpoints for screening phase II studies. Clin Cancer Res. 2009;15:1873–82.

    Article  CAS  PubMed  Google Scholar 

  62. Buyse M, Molenberghs G, Burzykowski T, Renard D, Geys H. The validation of surrogate endpoints in meta-analyses of randomized experiments. Biostatistics. 2000;1:49–67.

    Article  CAS  PubMed  Google Scholar 

  63. Daniels MJ, Hughes MD. Meta-analysis for the evaluation of potential surrogate markers. Stat Med. 1997;16:1965–82.

    Article  CAS  PubMed  Google Scholar 

  64. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med. 1998;17:2815–34.

    Article  CAS  PubMed  Google Scholar 

  65. Viele K, Connor JT. Dose-finding trials: Optimizing phase 2 data in the drug development process. JAMA. 2015;314:2294–5.

    Article  CAS  PubMed  Google Scholar 

  66. Turri M, Stein G. The determination of practically useful doses of new drugs: some methodological considerations. Stat Med. 1986;5:449–57.

    Article  CAS  PubMed  Google Scholar 

  67. Schmidt R. Dose-finding studies in clinical drug development. Eur J Clin Pharmacol. 1988;34:15–9.

    Article  CAS  PubMed  Google Scholar 

  68. Pinheiro J. Evaluation and recommendations on adaptive dose-ranging trials: highlights from the PhRMA Adaptive Dose-Ranging Studies Working Group. J Clin Pharmacol. 2010;50:47S-S49.

    Article  PubMed  Google Scholar 

  69. Bekele BN, Shen Y. A Bayesian approach to jointly modeling toxicity and biomarker expression in a phase I/II dose-finding trial. Biometrics. 2005;61:343–54.

    Article  PubMed  Google Scholar 

  70. Bornkamp B, Bretz F, Dmitrienko A, et al. Innovative approaches for designing and analyzing adaptive dose-ranging trials. J Biopharm Stat. 2007;17:965–95.

    Article  PubMed  Google Scholar 

  71. Abboud T, Andresen H, Koeppen J, et al. Serum levels of nimodipine in enteral and parenteral administration in patients with aneurysmal subarachnoid hemorrhage. Acta Neurochir (Wien). 2015;157:763–7.

    Article  Google Scholar 

  72. Soppi V, Kokki H, Koivisto T, et al. Early-phase pharmacokinetics of enteral and parenteral nimodipine in patients with acute subarachnoid haemorrhage - a pilot study. Eur J Clin Pharmacol. 2007;63:355–61.

    Article  CAS  PubMed  Google Scholar 

  73. Lees KR, Bluhmki E, von Kummer R, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010;375:1695–703.

    Article  CAS  PubMed  Google Scholar 

  74. Jabbarli R, Reinhard M, Niesen WD, et al. Predictors and impact of early cerebral infarction after aneurysmal subarachnoid hemorrhage. Eur J Neurol. 2015;22:941–7.

    Article  CAS  PubMed  Google Scholar 

  75. Ayling OG, Ibrahim GM, Alotaibi NM, Gooderham PA, Macdonald RL. Dissociation of early and delayed cerebral infarction after aneurysmal subarachnoid hemorrhage. Stroke. 2016;47:2945–51.

    Article  PubMed  Google Scholar 

  76. Hindman BJ, Bayman EO, Pfisterer WK, Torner JC, Todd MM, Investigators I. No association between intraoperative hypothermia or supplemental protective drug and neurologic outcomes in patients undergoing temporary clipping during cerebral aneurysm surgery: findings from the Intraoperative Hypothermia for Aneurysm Surgery Trial. Anesthesiology. 2010;112:86–101.

    Article  PubMed  Google Scholar 

  77. Hill MD, Martin RH, Mikulis D, et al. Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2012;11:942–50.

    Article  CAS  PubMed  Google Scholar 

  78. Macdonald RL, Higashida RT, Keller E, et al. Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke. 2012;43:1463–9.

    Article  CAS  PubMed  Google Scholar 

  79. Liang F, Wu Z, Mo M, et al. Comparison of treatment effect from randomised controlled phase II trials and subsequent phase III trials using identical regimens in the same treatment setting. Eur J Cancer. 2019;121:19–28.

    Article  PubMed  Google Scholar 

  80. Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2005;352:777–85.

    Article  CAS  PubMed  Google Scholar 

  81. Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2008;358:2127–37.

    Article  CAS  PubMed  Google Scholar 

  82. Palesch YY, Tilley BC, Sackett DL, Johnston KC, Woolson R. Applying a phase II futility study design to therapeutic stroke trials. Stroke. 2005;36:2410–4.

    Article  PubMed  Google Scholar 

  83. Yeatts SD. Novel methodologic approaches to phase I, II, and III trials. Stroke. 2013;44:S116–8.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Jung SH, George SL. Between-arm comparisons in randomized Phase II trials. J Biopharm Stat. 2009;19:456–68.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Yeatts SD, Palesch YY, Moy CS, Selim M. High dose deferoxamine in intracerebral hemorrhage (HI-DEF) trial: rationale, design, and methods. Neurocrit Care. 2013;19:257–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Dijkland SA, Jaja BNR, van der Jagt M, et al. Between-center and between-country differences in outcome after aneurysmal subarachnoid hemorrhage in the Subarachnoid Hemorrhage International Trialists (SAHIT) repository. J Neurosurg 2019:1–9.

  87. Qureshi AI, Tariq N, Vazquez G, et al. Low patient enrollment sites in multicenter randomized clinical trials of cerebrovascular diseases: associated factors and impact on trial outcomes. J Stroke Cerebrovasc Dis. 2012;21:131–42.

    Article  PubMed  Google Scholar 

  88. Guideline on adjustment for baseline covariates in clinical trials. 2015. (Accessed June 21, 2021, at https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-adjustment-baseline-covariates-clinical-trials_en.pdf.)

  89. Kahan BC. Accounting for centre-effects in multicentre trials with a binary outcome - when, why, and how? BMC Med Res Methodol. 2014;14:20.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Jaja BNR, Saposnik G, Lingsma HF, et al. Development and validation of outcome prediction models for aneurysmal subarachnoid haemorrhage: the SAHIT multinational cohort study. BMJ. 2018;360:j5745.

    Article  PubMed  Google Scholar 

  91. Langham J, Reeves BC, Lindsay KW, et al. Variation in outcome after subarachnoid hemorrhage: a study of neurosurgical units in UK and Ireland. Stroke. 2009;40:111–8.

    Article  PubMed  Google Scholar 

  92. Statements of probability and confidence intervals. (Accessed January 22, 2020, at https://www.bmj.com/about-bmj/resources-readers/publications/statistics-square-one/4-statements-probability-and-confiden.)

  93. Enrichment strategies for clinical trials to support determination of effectiveness of human drugs and biological products guidance for industry. 2019. (Accessed June 21, 2021, at https://www.fda.gov/media/121320/download#:~:text=Enrichment%20is%20the%20prospective%20use,be%20in%20an%20unselected%20population.)

  94. Kreiter KT, Mayer SA, Howard G, et al. Sample size estimates for clinical trials of vasospasm in subarachnoid hemorrhage. Stroke. 2009;40:2362–7.

    Article  PubMed  Google Scholar 

  95. Pond GR, Abbasi S. Quantitative evaluation of single-arm versus randomized phase II cancer clinical trials. Clin Trials. 2011;8:260–9.

    Article  PubMed  Google Scholar 

  96. Tang H, Foster NR, Grothey A, Ansell SM, Goldberg RM, Sargent DJ. Comparison of error rates in single-arm versus randomized phase II cancer clinical trials. J Clin Oncol. 2010;28:1936–41.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Taylor JM, Braun TM, Li Z. Comparing an experimental agent to a standard agent: relative merits of a one-arm or randomized two-arm Phase II design. Clin Trials. 2006;3:335–48.

    Article  PubMed  Google Scholar 

  98. Critical path initiative. 2018. (Accessed June 24, 2021, at https://www.fda.gov/science-research/science-and-research-special-topics/critical-path-initiative.)

  99. Chow SC, Chang M, Pong A. Statistical consideration of adaptive methods in clinical development. J Biopharm Stat. 2005;15:575–91.

    Article  PubMed  Google Scholar 

  100. Guidance for the use of bayesian statistics in medical device clinical trials. 2010. (Accessed September 20, 2021, at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-use-bayesian-statistics-medical-device-clinical-trials.)

  101. Korn EL, Freidlin B, Abrams JS, Halabi S. Design issues in randomized phase II/III trials. J Clin Oncol. 2012;30:667–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Adaptive seamless design for phase 2/3 studies: Basic concepts & considerations. 2018. (Accessed June 21, 2021, at https://www.clinicalleader.com/doc/adaptive-seamless-design-for-phase-studies-basic-concepts-considerations-0001.)

  103. Levin B, Thompson JL, Chakraborty B, Levy G, MacArthur R, Haley EC. Statistical aspects of the TNK-S2B trial of tenecteplase versus alteplase in acute ischemic stroke: an efficient, dose-adaptive, seamless phase II/III design. Clin Trials. 2011;8:398–407.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Shibuya M, Suzuki Y, Sugita K, et al. Dose escalation trial of a novel calcium antagonist, AT877, in patients with aneurysmal subarachnoid haemorrhage. Acta Neurochir (Wien). 1990;107:11–5.

    Article  CAS  Google Scholar 

  105. Shibuya M, Suzuki Y, Sugita K, et al. Effect of AT877 on cerebral vasospasm after aneurysmal subarachnoid haemorrhage. Results of a prospective placebo-controlled double-blind trial. J Neurosurg. 1992;76:571–7.

    Article  CAS  PubMed  Google Scholar 

  106. Kramer AH, Fletcher JJ. Locally-administered intrathecal thrombolytics following aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. Neurocrit Care. 2011;14:489–99.

    Article  PubMed  Google Scholar 

  107. Lu X, Ji C, Wu J, et al. Intrathecal fibrinolysis for aneurysmal subarachnoid hemorrhage: evidence from randomized controlled trials and cohort studies. Front Neurol. 2019;10:885.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Schuhlen H. Pre-specified vs. post-hoc subgroup analyses: are we wiser before or after a trial has been performed? Eur Heart J. 2014;35:2055–7.

    Article  PubMed  Google Scholar 

  109. Sun X, Briel M, Busse JW, et al. Credibility of claims of subgroup effects in randomised controlled trials: systematic review. BMJ. 2012;344:e1553.

    Article  PubMed  Google Scholar 

  110. Stroke Therapy Academic Industry R. Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 1999;30:2752–8.

  111. Liu S, Zhen G, Meloni BP, Campbell K, Winn HR. Rodent stroke model guidelines for preclinical stroke trials (1st edition). J Exp Stroke Transl Med 2009;2:2–27.

  112. Fisher M, Feuerstein G, Howells DW, et al. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke. 2009;40:2244–50.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Food, Drug Administration HHS. International conference on harmonisation; guidance on S9 nonclincal evaluation for anticancer pharmaceuticals; availability. Notice. Fed Regist 2010;75:10487–8.

  114. Allen GS, Ahn HS, Preziosi TJ, et al. Cerebral arterial spasm–a controlled trial of nimodipine in patients with subarachnoid hemorrhage. N Engl J Med. 1983;308:619–24.

    Article  CAS  PubMed  Google Scholar 

  115. Pickard JD, Murray GD, Illingworth R, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ. 1989;298:636–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Molyneux A, Kerr R, Stratton I, et al. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet. 2002;360:1267–74.

    Article  PubMed  Google Scholar 

  117. Liu PY, LeBlanc M, Desai M. False positive rates of randomized phase II designs. Control Clin Trials. 1999;20:343–52.

    Article  CAS  PubMed  Google Scholar 

  118. Clinical development success rates 2006–2015.. 2016. (Accessed June 21, 2021, at https://www.bio.org/sites/default/files/legacy/bioorg/docs/Clinical%20Development%20Success%20Rates%202006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016.pdf.)

  119. Savitz SI, Baron JC, Fisher M, Consortium SX. Stroke treatment academic industry roundtable X: Brain cytoprotection therapies in the reperfusion era. Stroke. 2019;50:1026–31.

    Article  Google Scholar 

  120. Hemorrhagic Stroke Academia Industry Roundtable P, Second HRP. Recommendations for clinical trials in ICH: The second hemorrhagic stroke academia industry roundtable. Stroke 2020;51:1333–8.

Download references

Funding

Dr. Qureshi has received consultation fees from AstraZeneca.

Author information

Authors and Affiliations

  1. Zeenat Qureshi Stroke Institutes and Department of Neurology, University of Missouri, One Hospital Dr. CE507, Columbia, MO, 65212, USA

    Adnan I. Qureshi, Iryna Lobanova, Wei Huang & Muhammad F. Ishfaq

  2. Department of Neurology and Rehabilitation Medicine, University of Cincinnati Gardner Neuroscience Institute, Cincinnati, OH, USA

    Joseph P. Broderick

  3. Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA

    Christy N. Cassarly & Renee H. Martin

  4. Department of Neurological Surgery, University of California San Francisco, Fresno, CA, USA

    R. Loch Macdonald

  5. Division of Neurosciences Critical Care, Departments of Anesthesiology and Critical Care Medicine, Neurology, and Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Jose I. Suarez

Authors
  1. Adnan I. Qureshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Iryna Lobanova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wei Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Muhammad F. Ishfaq
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Joseph P. Broderick
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christy N. Cassarly
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Renee H. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R. Loch Macdonald
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jose I. Suarez
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors participated in substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be published.

Corresponding author

Correspondence to Iryna Lobanova.

Ethics declarations

Conflicts of interest

All authors have no conflicts to disclose.

Ethical approval/informed consent

The manuscript adheres to ethical guidelines and indicates ethical approvals (institutional review board) and use of informed consent, as appropriate.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qureshi, A.I., Lobanova, I., Huang, W. et al. Lessons Learned from Phase II and Phase III Trials Investigating Therapeutic Agents for Cerebral Ischemia Associated with Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care 36, 662–681 (2022). https://doi.org/10.1007/s12028-021-01372-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12028-021-01372-4

Keywords

Search

Navigation