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Issues in Clinical Trial Design in Stem Cell Trials After Stroke

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Abstract

Increasing evidence suggests that stem cells and other restorative therapies have the potential to substantially reduce disability after stroke in humans. Evaluating such therapies in clinical trials introduces a number of complexities. Some of these are directly comparable to issues encountered in trials of acute stroke therapies, such as the need to stratify, train sites in endpoint measurement, and carefully select entry criteria in relation to preclinical study design. Other issues are more often encountered in the context of restorative therapies, such as the need for behavioral reinforcement and the utility of examining treatment benefits separately across different neural systems. The latter point emphasizes the potential importance of modality-specific endpoints. There are other issues that are specifically related to the use of biological therapies, such as measuring biological activity and identity prior to treatment. These issues are considered in the broader context of design of clinical trials examining stem cell therapies after stroke.

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References

  1. Adeoye O, Hornung R, Khatri P, Kleindorfer D. Recombinant tissue-type plasminogen activator use for ischemic stroke in the United States: a doubling of treatment rates over the course of 5 years. Stroke. 2011;42:1952–5.

    PubMed Central  CAS  PubMed  Google Scholar 

  2. Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, et al. Thrombolysis with alteplase 3–4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317–29.

    CAS  PubMed  Google Scholar 

  3. Tissue plasminogen activator for acute ischemic stroke. The national institute of neurological disorders and stroke rt-pa stroke study group. N Engl J Med. 1995;333:1581–7.

    Google Scholar 

  4. Grotta J, Bratina P. Subjective experiences of 24 patients dramatically recovering from stroke. Stroke. 1995;26:1285–8.

    CAS  PubMed  Google Scholar 

  5. Fisher M, Ratan R. New perspectives on developing acute stroke therapy. Ann Neurol. 2003;53:10–20.

    PubMed  Google Scholar 

  6. Philip M, Benatar M, Fisher M, Savitz SI. Methodological quality of animal studies of neuroprotective agents currently in phase ii/iii acute ischemic stroke trials. Stroke. 2009;40:577–81.

    CAS  PubMed  Google Scholar 

  7. Savitz SI, Fisher M. Future of neuroprotection for acute stroke: in the aftermath of the saint trials. Ann Neurol. 2007;61:396–402.

    CAS  PubMed  Google Scholar 

  8. Vu Q, Xie K, Eckert M, Zhao W, Cramer SC. Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke. Neurology. 2014;82:1277–86.

    PubMed Central  PubMed  Google Scholar 

  9. Cramer S. Clinical issues in animal models of stroke and rehabilitation. ILAR J/Nat Res Counc, Inst Lab Anim Resour. 2003;44:83–4.

    CAS  Google Scholar 

  10. Watanabe K, Bois FY, Zeise L. Interspecies extrapolation: a reexamination of acute toxicity data. Risk Anal. 1992;12:301–10.

    CAS  PubMed  Google Scholar 

  11. Davidson IW, Parker JC, Beliles RP. Biological basis for extrapolation across mammalian species. Regul Toxicol Pharmacol. 1986;6:211–37.

    CAS  PubMed  Google Scholar 

  12. Guidance for industry estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers USDoHaHSFaDA. 2005.

    Google Scholar 

  13. Li S, Carmichael ST. Growth-associated gene and protein expression in the region of axonal sprouting in the aged brain after stroke. Neurobiol Dis. 2006;23:362–73.

    CAS  PubMed  Google Scholar 

  14. Stroemer R, Kent T, Hulsebosch C. Enhanced neocortical neural sprouting, synaptogenesis, and behavioral recovery with d-amphetamine therapy after neocortical infarction in rats. Stroke. 1998;29:2381–95.

    CAS  PubMed  Google Scholar 

  15. Jones T, Schallert T. Overgrowth and pruning of dendrites in adult rats recovering from neocortical damage. Brain Res. 1992;581:156–60.

    CAS  PubMed  Google Scholar 

  16. Ren J, Kaplan P, Charette M, Speller H, Finklestein S. Time window of intracisternal osteogenic protein-1 in enhancing functional recovery after stroke. Neuropharmacology. 2000;39:860–5.

    CAS  PubMed  Google Scholar 

  17. Biernaskie J, Chernenko G, Corbett D. Efficacy of rehabilitative experience declines with time after focal ischemic brain injury. J Neurosci. 2004;24:1245–54.

    CAS  PubMed  Google Scholar 

  18. Winstein CJ, Wolf SL, Dromerick AW, Lane CJ, Nelsen MA, Lewthwaite R, et al. Interdisciplinary comprehensive arm rehabilitation evaluation (icare): a randomized controlled trial protocol. BMC Neurol. 2013;13:5.

    PubMed Central  PubMed  Google Scholar 

  19. Yozbatiran N, Der-Yeghiaian L, Cramer SC. A standardized approach to performing the action research arm test. Neurorehabil Neural Repair. 2008;22:78–90.

    PubMed  Google Scholar 

  20. See J, Dodakian L, Chou C, Chan V, McKenzie A, Reinkensmeyer DJ, et al. A standardized approach to the fugl-meyer assessment and its implications for clinical trials. Neurorehabil Neural Repair. 2013;27:732–41.

    PubMed  Google Scholar 

  21. Adkins-Muir D, Jones T. Cortical electrical stimulation combined with rehabilitative training: enhanced functional recovery and dendritic plasticity following focal cortical ischemia in rats. Neurol Res. 2003;25:780–8.

    PubMed  Google Scholar 

  22. Kleim J, Bruneau R, VandenBerg P, MacDonald E, Mulrooney R, Pocock D. Motor cortex stimulation enhances motor recovery and reduces peri-infarct dysfunction following ischemic insult. Neurol Res. 2003;25:789–93.

    PubMed  Google Scholar 

  23. Plautz E, Barbay S, Frost S, Friel K, Dancause N, Zoubina E, et al. Post-infarct cortical plasticity and behavioral recovery using concurrent cortical stimulation and rehabilitative training: a feasibility study in primates. Neurol Res. 2003;25:801–10.

    PubMed  Google Scholar 

  24. Teskey G, Flynn C, Goertzen C, Monfils M, Young N. Cortical stimulation improves skilled forelimb use following a focal ischemic infarct in the rat. Neurol Res. 2003;25:794–800.

    PubMed  Google Scholar 

  25. Levy R, Benson R, Winstein C, for the Everest Study Investigators. Cortical stimulation for upper-extremity hemiparesis from ischemic stroke: Everest study primary endpoint results. International Stroke Conference. 2008.

    Google Scholar 

  26. Nouri S, Cramer SC. Anatomy and physiology predict response to motor cortex stimulation after stroke. Neurology. 2011 Sep 13;77(11):1076–83.

    PubMed Central  PubMed  Google Scholar 

  27. Calautti C, Baron J. Functional neuroimaging studies of motor recovery after stroke in adults: a review. Stroke. 2003;34:1553–66.

    PubMed  Google Scholar 

  28. Cramer SC. Repairing the human brain after stroke. Ii. Restorative therapies. Ann Neurol. 2008;63:549–60.

    PubMed  Google Scholar 

  29. Lyden P, Lau G. A critical appraisal of stroke evaluation and rating scales. Stroke. 1991;22:1345–52.

    CAS  PubMed  Google Scholar 

  30. Gresham G, Duncan P, Stason W, Adams H, Adelman A, Alexander D, et al. Post-stroke rehabilitation. Rockville: U.S. Department of Health and Human Services. Public Health Service, Agency for Health Care Policy and Research; 1995.

    Google Scholar 

  31. Barak S, Duncan PW. Issues in selecting outcome measures to assess functional recovery after stroke. Neuro Rx. 2006;3:505–24.

    Google Scholar 

  32. Baker K, Cano SJ, Playford ED. Outcome measurement in stroke: a scale selection strategy. Stroke. 2011;42:1787–94.

    PubMed  Google Scholar 

  33. Lees KR, Bath PM, Schellinger PD, Kerr DM, Fulton R, Hacke W, et al. Contemporary outcome measures in acute stroke research: choice of primary outcome measure. Stroke. 2012;43:1163–70.

    PubMed  Google Scholar 

  34. World Health Organization. International classification of functioning, disability and health (icf). Geneva: World Health Organization; 2008.

    Google Scholar 

  35. Miller EL, Murray L, Richards L, Zorowitz RD, Bakas T, Clark P, et al. Comprehensive overview of nursing and interdisciplinary rehabilitation care of the stroke patient: a scientific statement from the American heart association. Stroke. 2010;41:2402–48.

    PubMed  Google Scholar 

  36. Wood-Dauphinee S, Williams J, Shapiro S. Examing outcome measures in a clinical study of stroke. Stroke. 1990;21:731–9.

    CAS  PubMed  Google Scholar 

  37. Dobkin B. The clinical science of neurologic rehabilitation. New York: Oxford University Press; 2003.

    Google Scholar 

  38. Cramer S, Nelles G, Schaechter J, Kaplan J, Finklestein S. Computerized measurement of motor performance after stroke. Stroke. 1997;28:2162–8.

    CAS  PubMed  Google Scholar 

  39. Stewart JC, Cramer SC. Patient-reported measures provide unique insights into motor function after stroke. Stroke. 2013;44:1111–6.

    PubMed Central  PubMed  Google Scholar 

  40. Duncan PW, Samsa GP, Weinberger M, Goldstein LB, Bonito A, Witter DM, et al. Health status of individuals with mild stroke. Stroke. 1997;28:740–5.

    CAS  PubMed  Google Scholar 

  41. Edwards DF, Hahn M, Baum C, Dromerick AW. The impact of mild stroke on meaningful activity and life satisfaction. J Stroke Cerebrovasc Dis. 2006;15:151–7.

    PubMed  Google Scholar 

  42. Carlsson GE, Moller A, Blomstrand C. Consequences of mild stroke in persons < 75 years–a 1-year follow-up. Cerebrovas Dis. (Basel, Switzerland). 2003;16:383–8.

    Google Scholar 

  43. Barrett AM. Rose-colored answers: neuropsychological deficits and patient-reported outcomes after stroke. Behav Neurol. 2010;22:17–23.

    PubMed  Google Scholar 

  44. Snyder CF, Aaronson NK, Choucair AK, Elliott TE, Greenhalgh J, Halyard MY, et al. Implementing patient-reported outcomes assessment in clinical practice: a review of the options and considerations. Qual Life Res. 2012 Oct;21(8):1305–14.

    Google Scholar 

  45. Department of Health. Equity and excellence: liberating the NHS. London: Department of Health; 2010.

    Google Scholar 

  46. Promis. Dynamic tools to measure health outcomes from the patient perspective. http://nihpromis.Org/. Zugegriffen: 01. Oct. 2014.

  47. Luce R, Narens L. Measurement scales on the continuum. Science. 1987;236:1527–32.

    CAS  PubMed  Google Scholar 

  48. Cramer SC, Koroshetz WJ, Finklestein SP. The case for modality-specific outcome measures in clinical trials of stroke recovery-promoting agents. Stroke. 2007;38:1393–5.

    PubMed  Google Scholar 

  49. Cramer SC, Fitzpatrick C, Warren M, Hill MD, Brown D, Whitaker L, et al. The beta-hcg+erythropoietin in acute stroke (betas) study: a 3-center, single-dose, open-label, noncontrolled, phase iia safety trial. Stroke. 2010;41:927–31.

    PubMed Central  CAS  PubMed  Google Scholar 

  50. Roth EJ, Heinemann AW, Lovell LL, Harvey RL, McGuire JR, Diaz S. Impairment and disability: their relation during stroke rehabilitation. Arch Phys Med Rehabil. 1998;79:329–35.

    CAS  PubMed  Google Scholar 

  51. Bath PM, Lees KR, Schellinger PD, Altman H, Bland M, Hogg C, et al. Statistical analysis of the primary outcome in acute stroke trials. Stroke. 2012;43:1171–8.

    PubMed  Google Scholar 

  52. Adams HP, Jr., Leclerc JR, Bluhmki E, Clarke W, Hansen MD, Hacke W. Measuring outcomes as a function of baseline severity of ischemic stroke. Cerebrovasc Dis (Basel, Switzerland). 2004;18:124–9.

    PubMed  Google Scholar 

  53. Duncan PW, Sullivan KJ, Behrman AL, Azen SP, Wu SS, Nadeau SE, et al. Body-weight-supported treadmill rehabilitation after stroke. N Engl J Med. 2011;364:2026–36.

    PubMed Central  CAS  PubMed  Google Scholar 

  54. Burke Quinlan E, Dodakian L, See J, McKenzie A, Le V, Wojnowicz M, et al. Neural function, injury, and stroke subtype predict treatment gains after stroke. Ann Neurol. 2015 Jan;77(1):132–45.

    Google Scholar 

  55. Hier D, Mondlock J, Caplan L. Recovery of behavioral abnormalities after right hemisphere stroke. Neurology. 1983;33:345–50.

    CAS  PubMed  Google Scholar 

  56. Marshall R, Perera G, Lazar R, Krakauer J, Constantine R, DeLaPaz R. Evolution of cortical activation during recovery from corticospinal tract infarction. Stroke. 2000;31:656–61.

    CAS  PubMed  Google Scholar 

  57. Markgraf C, Green E, Hurwitz B, Morikawa E, Dietrich W, McCabe P, et al. Sensorimotor and cognitive consequences of middle cerebral artery occlusion in rats. Brain Res. 1992;575:238–46.

    CAS  PubMed  Google Scholar 

  58. Fisher M, Hanley DF, Howard G, Jauch EC, Warach S. Recommendations from the stair v meeting on acute stroke trials, technology and outcomes. Stroke. 2007;38:245–8.

    PubMed  Google Scholar 

  59. Traynor K. Dalfampridine approved for ms. Am J Health Syst Pharm. 2010;67:335

    PubMed  Google Scholar 

  60. Feeney D, Gonzalez A, Law W. Amphetamine, halperidol, and experience interact to affect the rate of recovery after motor cortex injury. Science. 1982;217:855–7.

    CAS  PubMed  Google Scholar 

  61. Fang PC, Barbay S, Plautz EJ, Hoover E, Strittmatter SM, Nudo RJ. Combination of nep 1–40 treatment and motor training enhances behavioral recovery after a focal cortical infarct in rats. Stroke. 2010;41:544–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  62. Starkey ML, Schwab ME. Anti-nogo-a and training: Can one plus one equal three? Exp Neurol. 2012 May;235(1):53–61.

    PubMed  Google Scholar 

  63. Hovda D, Feeney D. Amphetamine with experience promotes recovery of locomotor function after unilateral frontal cortex injury in the cat. Brain Res. 1984;298:358–61.

    CAS  PubMed  Google Scholar 

  64. Adkins DL, Hsu JE, Jones TA. Motor cortical stimulation promotes synaptic plasticity and behavioral improvements following sensorimotor cortex lesions. Exp Neurol. 2008;212:14–28.

    PubMed Central  PubMed  Google Scholar 

  65. Kwakkel G. Impact of intensity of practice after stroke: issues for consideration. Disabil Rehabil. 2006;28:823–30.

    PubMed  Google Scholar 

  66. Kwakkel G, Wagenaar R, Twisk J, Lankhorst G, Koetsier J. Intensity of leg and arm training after primary middle-cerebral-artery stroke: a randomised trial. Lancet. 1999;354:191–6.

    CAS  PubMed  Google Scholar 

  67. Van Peppen RP Kwakkel G Wood-Dauphinee S Hendriks HJ Van der Wees PJ Dekker J. The impact of physical therapy on functional outcomes after stroke: What’s the evidence? Clin Rehabil. 2004;18:833–62.

    PubMed  Google Scholar 

  68. Cicerone KD, Dahlberg C, Malec JF, Langenbahn DM, Felicetti T, Kneipp S, et al. Evidence-based cognitive rehabilitation: updated review of the literature from 1998 through 2002. Arch Phys Med Rehabil. 2005;86:1681–92.

    PubMed  Google Scholar 

  69. Bhogal S, Teasell R, Speechley M. Intensity of aphasia therapy, impact on recovery. Stroke. 2003;34:987–93.

    PubMed  Google Scholar 

  70. Jones T, Chu C, Grande L, Gregory A. Motor skills training enhances lesion-induced structural plasticity in the motor cortex of adult rats. J Neurosci. 1999;19:10153–63.

    CAS  PubMed  Google Scholar 

  71. Johansson B. Brain plasticity and stroke rehabilitation. The willis lecture. Stroke. 2000;31:223–30.

    CAS  PubMed  Google Scholar 

  72. Smith J, Forster A, Young J. Cochrane review: information provision for stroke patients and their caregivers. Clin Rehabil. 2009;23:195–206.

    PubMed  Google Scholar 

  73. Glass TA, Matchar DB, Belyea M, Feussner JR. Impact of social support on outcome in first stroke. Stroke. 1993;24:64–70.

    CAS  PubMed  Google Scholar 

  74. Lai SM, Duncan PW, Keighley J, Johnson D. Depressive symptoms and independence in badl and iadl. J Rehabil Res Dev. 2002;39:589–96.

    PubMed  Google Scholar 

  75. Jonsson AC, Lindgren I, Hallstrom B, Norrving B, Lindgren A. Determinants of quality of life in stroke survivors and their informal caregivers. Stroke. 2005;36:803–8.

    PubMed  Google Scholar 

  76. Mukherjee D, Levin RL, Heller W. The cognitive, emotional, and social sequelae of stroke: Psychological and ethical concerns in post-stroke adaptation. Top Stroke Rehabil. 2006;13:26–35.

    PubMed  Google Scholar 

  77. McFadden E, Luben R, Wareham N, Bingham S, Khaw KT. Social class, risk factors, and stroke incidence in men and women: a prospective study in the European prospective investigation into cancer in norfolk cohort. Stroke. 2009;40:1070–7.

    PubMed  Google Scholar 

  78. Cramer S, Dobkin B, Noser E, Rodriguez R, Enney L. A randomized, placebo-controlled, double-blind study of ropinirole in chronic stroke. Stroke. 2009 Sep;40(9):3034–8.

    CAS  PubMed  Google Scholar 

  79. Cramer SC. Stratifying patients with stroke in trials that target brain repair. Stroke. 2010;41:S114–6.

    PubMed  Google Scholar 

  80. Stinear CM, Barber PA, Smale PR, Coxon JP, Fleming MK, Byblow WD. Functional potential in chronic stroke patients depends on corticospinal tract integrity. Brain. 2007;130:170–80.

    PubMed  Google Scholar 

  81. Lindenberg R, Zhu LL, Ruber T, Schlaug G. Predicting functional motor potential in chronic stroke patients using diffusion tensor imaging. Hum Brain Mapp. 2012;33:1040–51.

    PubMed Central  PubMed  Google Scholar 

  82. Riley JD, Le V, Der-Yeghiaian L, See J, Newton JM, Ward NS, et al. Anatomy of stroke injury predicts gains from therapy. Stroke. 2011;42:421–6.

    PubMed Central  PubMed  Google Scholar 

  83. Stinear CM, Barber PA, Petoe M, Anwar S, Byblow WD. The prep algorithm predicts potential for upper limb recovery after stroke. Brain: J Neurol. 2012;135:2527–35.

    Google Scholar 

  84. Dong Y, Dobkin BH, Cen SY, Wu AD, Winstein CJ. Motor cortex activation during treatment may predict therapeutic gains in paretic hand function after stroke. Stroke. 2006;37:1552–5.

    PubMed  Google Scholar 

  85. Milot MH, Spencer SJ, Chan V, Allington JP, Klein J, Chou C, et al. Corticospinal excitability as a predictor of functional gains at the affected upper limb following robotic training in chronic stroke survivors. Neurorehabil Neural Repair. 2014 Nov-Dec;28(9):819–27.

    PubMed  Google Scholar 

  86. Cramer SC, Parrish TB, Levy RM, Stebbins GT, Ruland SD, Lowry DW, et al. Predicting functional gains in a stroke trial. Stroke. 2007;38:2108–14.

    Google Scholar 

  87. Laible M, Grieshammer S, Seidel G, Rijntjes M, Weiller C, Hamzei F. Association of activity changes in the primary sensory cortex with successful motor rehabilitation of the hand following stroke. Neurorehabil Neural Repair. 2012;26:881–8.

    PubMed  Google Scholar 

  88. Sergi F, Krebs HI, Groissier B, Rykman A, Guglielmelli E, Volpe BT, et al. Predicting efficacy of robot-aided rehabilitation in chronic stroke patients using an mri-compatible robotic device. Conference proceedings:… annual international conference of the IEEE engineering in medicine and biology society. IEEE engineering in medicine and biology society. Conference. 2011;2011:7470–3.

    Google Scholar 

  89. Varkuti B, Guan C, Pan Y, Phua KS, Ang KK, Kuah CW, et al. Resting state changes in functional connectivity correlate with movement recovery for bci and robot-assisted upper-extremity training after stroke. Neurorehabil Neural Repair. 2013;27:53–62.

    PubMed  Google Scholar 

  90. Graham JE, Ripsin CM, Deutsch A, Kuo YF, Markello S, Granger CV, et al. Relationship between diabetes codes that affect medicare reimbursement (tier comorbidities) and outcomes in stroke rehabilitation. Arch Phys Med Rehabil. 2009;90:1110–6.

    PubMed Central  PubMed  Google Scholar 

  91. Dam M, Tonin P, Casson S, Ermani M, Pizzolato G, Iaia V, et al. The effects of long-term rehabilitation therapy on poststroke hemiplegic patients. Stroke. 1993;24:1186–91.

    CAS  PubMed  Google Scholar 

  92. Kononen M, Tarkka IM, Niskanen E, Pihlajamaki M, Mervaala E, Pitkanen K, et al. Functional mri and motor behavioral changes obtained with constraint-induced movement therapy in chronic stroke. Eur J Neurol. 2012;19:578–86.

    CAS  PubMed  Google Scholar 

  93. Gillen R, Tennen H, McKee TE, Gernert-Dott P, Affleck G. Depressive symptoms and history of depression predict rehabilitation efficiency in stroke patients. Arch Phys Med Rehabil. 2001;82:1645–9.

    CAS  PubMed  Google Scholar 

  94. McCarron MO, Muir KW, Nicoll JA, Stewart J, Currie Y, Brown K, et al. Prospective study of apolipoprotein e genotype and functional outcome following ischemic stroke. Arch Neurol. 2000;57:1480–4.

    CAS  PubMed  Google Scholar 

  95. Cramer SC, Procaccio V. Correlation between genetic polymorphisms and stroke recovery: analysis of the gain Americas and gain international studies. Eur J Neurol. 2012;19:718–24.

    CAS  PubMed  Google Scholar 

  96. Pearson-Fuhrhop KM, Burke E, Cramer SC. The influence of genetic factors on brain plasticity and recovery after neural injury. Curr Opin Neurol. 2012 Dec;25(6):682–8.

    PubMed  Google Scholar 

  97. Siironen J, Juvela S, Kanarek K, Vilkki J, Hernesniemi J, Lappalainen J. The met allele of the bdnf val66met polymorphism predicts poor outcome among survivors of aneurysmal subarachnoid hemorrhage. Stroke. 2007;38:2858–60.

    CAS  PubMed  Google Scholar 

  98. Freburger JK, Holmes GM, Ku LJ, Cutchin MP, Heatwole-Shank K, Edwards LJ. Disparities in postacute rehabilitation care for stroke: an analysis of the state inpatient databases. Arch Phys Med Rehabil. 2011;92:1220–9.

    PubMed Central  PubMed  Google Scholar 

  99. Burke E, Cramer SC. Biomarkers and predictors of restorative therapy effects after stroke. Curr Neurol Neurosci Rep. 2013;13:329.

    PubMed Central  PubMed  Google Scholar 

  100. Toth G, Albers GW. Use of mri to estimate the therapeutic window in acute stroke: is perfusion-weighted imaging/diffusion-weighted imaging mismatch an epithet for salvageable ischemic brain tissue? Stroke. 2009;40:333–5.

    PubMed  Google Scholar 

  101. Donnan GA, Baron JC, Ma H, Davis SM. Penumbral selection of patients for trials of acute stroke therapy. Lancet Neurol. 2009;8:261–9.

    CAS  PubMed  Google Scholar 

  102. Feuerstein GZ, Zaleska MM, Krams M, Wang X, Day M, Rutkowski JL, et al. Missing steps in the stair case: a translational medicine perspective on the development of nxy-059 for treatment of acute ischemic stroke. J Cereb Blood Flow Metab. 2008;28:217–9.

    CAS  PubMed  Google Scholar 

  103. Carey J, Kimberley T, Lewis S, Auerbach E, Dorsey L, Rundquist P, et al. Analysis of fmri and finger tracking training in subjects with chronic stroke. Brain. 2002;125:773–88.

    PubMed  Google Scholar 

  104. Johansen-Berg H, Dawes H, Guy C, Smith S, Wade D, Matthews P. Correlation between motor improvements and altered fmri activity after rehabilitative therapy. Brain. 2002;125:2731–42.

    PubMed  Google Scholar 

  105. Koski L, Mernar T, Dobkin B. Immediate and long-term changes in corticomotor output in response to rehabilitation: correlation with functional improvements in chronic stroke. Neurorehabil Neural Repair. 2004;18:230–49.

    PubMed  Google Scholar 

  106. Milot MH, Cramer SC. Biomarkers of recovery after stroke. Curr Opin Neurol. 2008;21:654–9.

    PubMed  Google Scholar 

  107. Fleming T, DeMets D. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996;125:605–13.

    CAS  PubMed  Google Scholar 

  108. Bucher H, Guyatt G, Cook D, Holbrook A, McAlister F. Users’ guides to the medical literature: Xix. Applying clinical trial results. A. How to use an article measuring the effect of an intervention on surrogate end points? Evidence-based medicine working group. JAMA. 1999;282:771–8.

    CAS  PubMed  Google Scholar 

  109. Geiger S, Holdenrieder S, Stieber P, Hamann GF, Bruening R, Ma J, et al. Nucleosomes as a new prognostic marker in early cerebral stroke. J Neurol. 2007;254:617–23.

    PubMed  Google Scholar 

  110. Yip HK, Chang LT, Chang WN, Lu CH, Liou CW, Lan MY, et al. Level and value of circulating endothelial progenitor cells in patients after acute ischemic stroke. Stroke. 2008;39:69–74.

    PubMed  Google Scholar 

  111. Brott T, Marler J, Olinger C, Adams H, Tomsick T, Barsan W, et al. Measurements of acute cerebral infarction: lesion size by computed tomography. Stroke. 1989;20:871–5.

    CAS  PubMed  Google Scholar 

  112. Schaechter JD, Moore CI, Connell BD, Rosen BR, Dijkhuizen RM. Structural and functional plasticity in the somatosensory cortex of chronic stroke patients. Brain. 2006;129:2722–33.

    PubMed  Google Scholar 

  113. Ding G, Jiang Q, Li L, Zhang L, Zhang ZG, Ledbetter KA, et al. Magnetic resonance imaging investigation of axonal remodeling and angiogenesis after embolic stroke in sildenafil-treated rats. J Cereb Blood Flow Metab. 2008;28:1440–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  114. Lindenberg R, Zhu LL, Ruber T, Schlaug G. Predicting functional motor potential in chronic stroke patients using diffusion tensor imaging. Hum Brain Mapp. 2012 May;33(5):1040–51.

    PubMed Central  PubMed  Google Scholar 

  115. Marchina S, Zhu LL, Norton A, Zipse L, Wan CY, Schlaug G. Impairment of speech production predicted by lesion load of the left arcuate fasciculus. Stroke. 2011;42:2251–6.

    PubMed Central  PubMed  Google Scholar 

  116. Hodics T, Cohen LG, Cramer SC. Functional imaging of intervention effects in stroke motor rehabilitation. Arch Phys Med Rehabil. 2006;87:36–42.

    Google Scholar 

  117. Richards LG, Stewart KC, Woodbury ML, Senesac C, Cauraugh JH. Movement-dependent stroke recovery: a systematic review and meta-analysis of tms and fmri evidence. Neuropsychologia. 2008;46:3–11.

    PubMed Central  PubMed  Google Scholar 

  118. Carter AR, Astafiev SV, Lang CE, Connor LT, Rengachary J, Strube MJ, et al. Resting interhemispheric functional magnetic resonance imaging connectivity predicts performance after stroke. Ann Neurol. 2010;67:365–75.

    PubMed Central  PubMed  Google Scholar 

  119. Parsons M, Li T, Barber P, Yang Q, Darby D, Desmond P, et al. Combined (1)h mr spectroscopy and diffusion-weighted mri improves the prediction of stroke outcome. Neurology. 2000;55:498–505.

    CAS  PubMed  Google Scholar 

  120. Pendlebury S, Blamire A, Lee M, Styles P, Matthews P. Axonal injury in the internal capsule correlates with motor impairment after stroke. Stroke. 1999;30:956–62.

    CAS  PubMed  Google Scholar 

  121. Talelli P, Greenwood RJ, Rothwell JC. Arm function after stroke: neurophysiological correlates and recovery mechanisms assessed by transcranial magnetic stimulation. Clin Neurophysiol. 2006;117:1641–59.

    CAS  PubMed  Google Scholar 

  122. Crafton K, Mark A, Cramer S. Improved understanding of cortical injury by incorporating measures of functional anatomy. Brain. 2003;126:1650–9.

    PubMed  Google Scholar 

  123. Bocti C, Swartz RH, Gao FQ, Sahlas DJ, Behl P, Black SE. A new visual rating scale to assess strategic white matter hyperintensities within cholinergic pathways in dementia. Stroke. 2005;36:2126–31.

    PubMed  Google Scholar 

  124. Hillis AE, Gold L, Kannan V, Cloutman L, Kleinman JT, Newhart M, et al. Site of the ischemic penumbra as a predictor of potential for recovery of functions. Neurology. 2008;71:184–9.

    CAS  PubMed  Google Scholar 

  125. Hyun I. The bioethics of stem cell research and therapy. J Clin Invest. 2010;120:71–5.

    PubMed Central  CAS  PubMed  Google Scholar 

  126. Food and Drug Administration Center for Biologics Evaluation and Research. Guidance for industry potency tests for cellular and gene therapy products. http://www.Fda.Gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/cellularandgenetherapy/ucm243392.Pdf. 2011. Accessed 1 March 2015.

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  1. Department of Neurology, Anatomy and Neurobiology, and Physical Medicine and Rehabilitation, Institute for Clinical and Translational Science, Sue and Bill Gross Stem Cell Research Center, UC Irvine Medical Center, University of California, Irvine, 200 S. Manchester Ave. Suite 206, 92868, Orange, CA, USA

    Steven C. Cramer MD

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  1. Steven C. Cramer MD
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Correspondence to Steven C. Cramer MD .

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  1. Department of Neurology, Georgia Regents University, Augusta, Georgia, USA

    David C. Hess

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Cramer, S. (2015). Issues in Clinical Trial Design in Stem Cell Trials After Stroke. In: Hess, D. (eds) Cell Therapy for Brain Injury. Springer, Cham. https://doi.org/10.1007/978-3-319-15063-5_18

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