Thoughts About the Negative Results of Clinical Trials in Rehabilitation Medicine

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The last decade has witnessed an increase in the number of moderate to large-scale nonpharmacologic stroke recovery trials. While a majority, having tested the superiority of a particular evidence-based intervention, returned negative findings, the rehabilitation research community has gained an important perspective for future efforts. We offer our interpretation first, on why most of the past decade’s trials failed in the sense of not supporting the primary superiority hypothesis, and, second, we provide our perspective on how to solve this problem and thereby inform the next generation of neurorehabilitation clinical trials. The first large-scale randomized controlled trial (RCT) ever conducted in neurorehabilitation was the Extremity Constraint Induced Movement Therapy Evaluation (EXCITE) trial. The majority of stroke recovery trials that followed were based on a prevailing, but as yet immature science of brain-behavior mechanisms for recovery and limited practical know-how about how to select the most meaningful outcomes. The research community had been seduced by a set of preclinical studies, ignited by the 1990’s revolution in neuroscience and an oversimplified premise that high doses of task-oriented training was the most important ingredient to foster recovery. Here, we highlight recent qualitative and quantitative evidence, both mechanistic and theory-driven, that integrates crucial social and personal factors to inform a more mature science better suited for the next generation of recovery-supportive rehabilitation clinical trials.

Winstein is with the Division of Biokinesiology & Physical Therapy, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA; and also with the Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA.

Address author correspondence to Carolee Winstein at Winstein@pt.usc.edu.
  • Adkins, D.L., Schallert, T., & Goldstein, L.B. (2009). Poststroke treatment: Lost in translation. Stroke: A Journal of Cerebral Circulation, 40(1), 89. doi:10.1161/STROKEAHA.108.534248

    • Crossref
    • Search Google Scholar
    • Export Citation
  • AVERT. (2015). Efficacy and safety of very early mobilisation within 24 h of stroke onset (AVERT): A randomised controlled trial. The Lancet, 6736(15), 110. doi:10.1016/S0140-6736(15)60690-0

    • Search Google Scholar
    • Export Citation
  • Barker, R.N., Gill, T.J., & Brauer, S.G. (2007). Factors contributing to upper limb recovery after stroke: A survey of stroke survivors in Queensland Australia. Disability and Rehabilitation, 29(13), 981989. PubMed doi:10.1080/09638280500243570

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bernhardt, J., Borschmann, K., Boyd, L., Thomas Carmichael, S., Corbett, D., Cramer, S.C., … Ward, N. (2016). Moving rehabilitation research forward: Developing consensus statements for rehabilitation and recovery research. International Journal of Stroke, 11(4), 454458. PubMed doi:10.1177/1747493016643851

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Bernhardt, J., Churilov, L., Ellery, F., Collier, J., Chamberlain, J., Langhorne, P., … AVERT Collaboration Group. (2016). Prespecified dose-response analysis for A Very Early Rehabilitation Trial (AVERT). Neurology 86(23), 21382145. doi:10.1212/WNL.0000000000002459

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Black, N. (2013). Patient reported outcome measures could help transform healthcare. British Medical Journal, 346(1), 167. doi:10.1136/bmj.f167

  • Campbell, M., Fitzpatrick, R., Haines, A., Kinmonth, A.L., Sandercock, P., Spiegelhalter, D., & Tyrer, P. (2000). Framework for design and evaluation of complex interventions to improve health. British Medical Journal 321(7262), 694696. PubMed doi:10.1136/bmj.321.7262.694

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Corbett, D., Jeffers, M., Nguemeni, C., Gomez-Smith, M., & Livingston-Thomas, J. (2015). Lost in translation. Progress in Brain Research, 218, 413434. doi:10.1016/bs.pbr.2014.12.002

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Cramer, S.C., Wolf, S.L., Adams, H.P., Chen, D., Dromerick, A.W., Dunning, K., … Broderick, J.P. (2017). Stroke recovery and rehabilitation research. Stroke 48(3), 813819. PubMed doi:10.1161/STROKEAHA.116.015501

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Danks, K.A., Pohlig, R.T., Roos, M., Wright, T.R., & Reisman, D.S. (2016). Relationship between walking capacity, biopsychosocial factors, self-efficacy, and walking activity in persons poststroke. Journal of Neurologic Physical Therapy, 40(4), 232238. PubMed doi:10.1097/NPT.0000000000000143

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Dobkin, B.H. (2017). A rehabilitation-internet-of-things in the home to augment motor skills and exercise training. Neurorehabilitation and Neural Repair, 31(3), 217227. PubMed doi:10.1177/1545968316680490

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Dobkin, B.H., & Carmichael, S.T. (2016). The specific requirements of neural repair trials for stroke. Neurorehabilitation and Neural Repair, 30(5), 470478. PubMed doi:10.1177/1545968315604400

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Dromerick, A.W., Lang, C.E., Birkenmeier, R., Wagner, J.M., Miller, J.P., Videen, T.O., … Edwards, D.F. (2009). Very Early Constraint-Induced Movement during Stroke Rehabilitation (VECTORS): A single-center RCT. Neurology, 73, 195201. PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Duncan, P.W., Sullivan, K.J., Behrman, A.L., Azen, S.P., Wu, S.S., Nadeau, S.E., … Hayden, S.K. (2011). Body-weight-supported treadmill rehabilitation after stroke. The New England Journal of Medicine, 364(21), 20262036. PubMed doi:10.1056/NEJMoa1010790

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Edwards, D.F., Hahn, M., Baum, C., & Dromerick, A.W. (2006). The impact of mild stroke on meaningful activity and life satisfaction. Journal of Stroke and Cerebrovascular Diseases, 15, 151157. PubMed doi:10.1016/j.jstrokecerebrovasdis.2006.04.001

    • Crossref
    • Search Google Scholar
    • Export Citation
  • French, M.A., Moore, M.F., Pohlig, R., & Reisman, D. (2015). Self-efficacy mediates the relationship between balance/walking performance, activity, and participation after stroke. Topics in Stroke Rehabilitation, 9357(July), 17. doi:10.1080/10749357.2015.1110306

    • Search Google Scholar
    • Export Citation
  • Gauthier, L.V, Taub, E., Perkins, C., Ortmann, M., Mark, V.W., & Uswatte, G. (2008). Remodeling the brain: Plastic structural brain changes produced by different motor therapies after stroke * supplemental material. Stroke 39(5), 15201525. PubMed doi:10.1161/strokeaha.107.502229

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Han, C.E., Arbib, M.A., & Schweighofer, N. (2008). Stroke rehabilitation reaches a threshold. PLoS Computational Biology 4(8), e1000133. doi:10.1371/journal.pcbi.1000133

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hidaka, Y., Han, C.E., Wolf, S.L., Winstein, C.J., & Schweighofer, N. (2012). Use it and improve it or lose it: Interactions between arm function and use in humanspost-stroke. PLoS Computational Biology, 8(2), e1002343.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Insel, T.R., & Landis, S.C. (2013). Twenty-five years of progress: The view from NIMH and NINDS. Neuron, 80(3), 561567. PubMed doi:10.1016/j.neuron.2013.09.041

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Institute of Medicine. (2001). Crossing the quality chasm: A new health system for the 21th century (pp. 18). Washington, DC: The National Academies Press. doi:10.17226/10027

    • Search Google Scholar
    • Export Citation
  • Institute of Medicine. (2012). Envisioning a transformed clinical trials enterprise in the United States: Establishing an agenda for 2020. (T. N. A. Press, Ed.). Washington, DC: Author.

    • Search Google Scholar
    • Export Citation
  • Jolkkonen, J., & Kwakkel, G. (2016). Translational hurdles in stroke recovery studies. Translational Stroke Research, 7(4), 331342. doi:10.1007/s12975-016-0461-y

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kayes, N.M., & McPherson, K.M. (2010). Measuring what matters: Does “objectivity” mean good science? Disability and Rehabilitation, 32(12), 10111019. PubMed doi:10.3109/09638281003775501

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kleim, J.A., Jones, T.A., & Schallert, T. (2003). Motor enrichment and the induction of plasticity before or after brain injury. Neurochemical Research, 28(11), 17571769. PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kwakkel, G., Lannin, N.A., Borschmann, K., English, C., Ali, M., Churilov, L., … Bernhardt, J. (2017). Standardized measurement of sensorimotor recovery in stroke trials: Consensus-based core recommendations from the Stroke Recovery and Rehabilitation Roundtable. International Journal of Stroke, 12(5), 451461. PubMed doi:10.1177/1747493017711813

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Kwakkel, G., Winters, C., van Wegen, E.E.H., Nijland, R.H.M., van Kuijk, A.A.A., Visser-Meily, A., … EXPLICIT-Stroke Consortium. (2016). Effects of unilateral upper limb training in two distinct prognostic groups early after stroke: The EXPLICIT-stroke randomized clinical trial. Neurorehabilitation and Neural Repair, 30(9), 804816. PubMed doi:10.1177/1545968315624784

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lang, C.E., Strube, M.J., Bland, M.D., Waddell, K.J., Cherry-Allen, K.M., Nudo, R.J., … Birkenmeier, R.L. (2016). Dose response of task-specific upper limb training in people at least 6 months poststroke: A phase II, single-blind, randomized, controlled trial. Annals of Neurology, 80(3), 342354. doi:10.1002/ana.24734

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Levine, P., & Page, S.J. (2004). Modified constraint-induced therapy: A promising restorative outpatient therapy. Topics in Stroke Rehabilitation, 11(4), 110. PubMed doi:10.1310/R4HN-51MW-JFYK-2JAN

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Levy, R.M., Harvey, R.L., Kissela, B.M., Winstein, C.J., Lutsep, H.L., Parrish, T.B., … Venkatesan, L. (2016). Epidural electrical stimulation for stroke rehabilitation: Results of the prospective, multicenter, randomized, single-blinded Everest trial. Neurorehabilitation and Neural Repair, 30(2), 107119. PubMed doi:10.1177/1545968315575613

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lewthwaite, R., Chiviacowsky, S., Drews, R., & Wulf, G. (2015). Choose to move: The motivational impact of autonomy support on motor learning. Psychonomic Bulletin & Review, 22(5), 13831388. PubMed doi:10.3758/s13423-015-0814-7

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lindley, R.I., Anderson, C.S., Billot, L., Forster, A., Hackett, M.L., Harvey, L.A., … Sebastian, I. (2017). Family-led rehabilitation after stroke in India (ATTEND): A randomised controlled trial. The Lancet, 390(10094), 588599. doi:10.1016/S0140-6736(17)31447-2

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Lo, A.C., Guarino, P.D., Richards, L.G., Haselkorn, J.K., Wittenberg, G.F., Federman, D.G., … Peduzzi, P. (2010). Robot-assisted therapy for long-term upper-limb impairment after stroke. The New England Journal of Medicine, 362(19), 17721783. doi:10.1056/NEJMoa0911341

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Luft, A.R., & Hanley, D.F. (2006). Stroke recovery—moving in an EXCITE-ing direction. The Journal of the American Medical Association 296(17), 21412143. PubMed

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Luker, J., Lynch, E., Bernhardsson, S., Bennett, L., & Bernhardt, J. (2015). Stroke survivors’ experiences of physical rehabilitation: A systematic review of qualitative studies. Archives of Physical Medicine and Rehabilitation, 96(9), 16981708. PubMed doi:10.1016/j.apmr.2015.03.017

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Page, S.J., & Levine, P. (2007). Modified constraint-induced therapy in patients with chronic stroke exhibiting minimal movement ability in the affected arm. Physical Theraphy, 87(7), 872878. doi:10.2522/ptj.2007.87.11.1559.2

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Page, S.J., Levine, P., & Leonard, A.C. (2005). Modified constraint-induced therapy in acute stroke: A randomized controlled pilot study. Neurorehabilitation and Neural Repair, 19(1), 2732. PubMed doi:10.1177/1545968304272701

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Page, S.J., Sisto, S., Johnston, M.V., & Levine, P. (2002). Modified constraint-induced therapy after subacute stroke: A preliminary study. Neurorehabilitation and Neural Repair, 16(3), 290295. PubMed doi:10.1177/154596830201600307

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Pedan, C.J., & Saxon, L.A. (2017). Patient engagement: Digital technology to engage patients: Ensuring access for all. NEJM Catalyst, 12. Retrieved from https://catalyst.nejm.org/digital-health-technology-access/

    • Search Google Scholar
    • Export Citation
  • Reuben, D.B., & Tinetti, M.E. (2012). Goal-oriented patient care—an alternative health outcomes paradigm. The New England Journal of Medicine, 366, 777779. doi:10.1056/NEJMp1113631

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Rosbergen, I., Grimley, R.S., Hayward, K.S., Walke, K.C., Rowley, D., Campbell, A.M., … Brauer, S.G. (2016). Embedding an enriched environment in an acute stroke unit increases activity in people with stroke: Results of a pilot study. Cerebrovascular Diseases, 42, 7. doi:10.1177/0269215517705181

    • Search Google Scholar
    • Export Citation
  • Rosenbaum, L. (2013). The whole ball game—overcoming the blind spots in health care reform. The New England Journal of Medicine, 368(10), 959962. doi:10.1056/NEJMms1301576

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Sabini, R.C., Dijkers, M.P., & Raghavan, P. (2013). Stroke survivors talk while doing: Development of a therapeutic framework for continued rehabilitation of hand function post stroke. Journal of Hand Theraphy, 26(2), 124130; quiz 131. doi:10.1016/j.jht.2012.08.002

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Schuch, C.P., Jeffers, M.S., Antonescu, S., Nguemeni, C., Gomez-Smith, M., Pereira, L.O., … Corbett, D. (2016). Enriched rehabilitation promotes motor recovery in rats exposed to neonatal hypoxia-ischemia. Behavioural Brain Research, 304, 4250. PubMed doi:10.1016/j.bbr.2016.02.010

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Stone, A. (2007). The science of real-time data capture. New York, NY: Oxford University Press.

  • Taub, E., Lum, P.S., Hardin, P., Mark, V.W., & Uswatte, G. (2005). AutoCITE: Automated delivery of CI therapy with reduced effort by therapists. Stroke 36(6), 13011304. PubMed doi:10.1161/01.STR.0000166043.27545.e8

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • Taule, T., & Råheim, M. (2014). Life changed existentially: A qualitative study of experiences at 6-8 months after mild stroke. Disability and Rehabilitation, 36, 113. doi:10.3109/09638288.2014.904448

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Tennant, K.A., Adkins, D.L., Scalco, M.D., Donlan, N.A., Asay, A.L., Thomas, N., … Jones, T.A. (2012). Skill learning induced plasticity of motor cortical representations is time and age-dependent. Neurobiology of Learning and Memory, 98, 291302.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Timmermans, A.A., Spooren, A.I., Kingma, H., & Seelen, H.A. (2010). Influence of task-oriented training content on skilled arm-hand performance in stroke: A systematic review. Neurorehabilitation and Neural Repair, 24(9), 858870. doi:10.1177/1545968310368963

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Valero-Cuevas, F.J., Klamroth-Marganska, V., Winstein, C.J., & Riener, R. (2016). Robot-assisted and conventional therapies produce distinct rehabilitative trends in stroke survivors. Journal of NeuroEngineering and Rehabilitation, 13(1), 92. PubMed doi:10.1186/s12984-016-0199-5

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wagle, N.W. (2016). Implementing Patient-Reported Outcome Measures (PROMs). NEJM Catalyst, 12. Retrieved from http://catalyst.nejm.org/implementing-proms-patient-reported-outcome-measures/

    • Search Google Scholar
    • Export Citation
  • Winstein, C.J., Blanton, S.R., Wolf, L.B., & Wishart, L. (2014). Infusing motor learning research into neurorehabilitation practice: A historical perspective with case exemplar from the Accelerated Skill Acquisition Program. Journal of Neurologic Physical Therapy, 38(3), 190200. doi:10.1097/NPT.0000000000000046

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Winstein, C.J., & Kay, D.B. (2015). Translating the science into practice: Shaping rehabilitation practice to enhance recovery after brain damage. In N. Dancause & S. Rossignol (Eds.), Sensorimotor rehabilitation: At the crossroads of basic and clinical sciences (Vol. 218, pp. 331360). Amsterdam, The Netherlands: Elsevier B.V. doi:10.1016/bs.pbr.2015.01.004

    • Search Google Scholar
    • Export Citation
  • Winstein, C.J., & Wolf, S.L. (2008). Task-oriented training to promote upper extremity recovery. In J. Stein, R.L. Harvey, R.F. Macko, C.J. Winstein, & R.D. Zorowitz (Eds.), Stroke recovery and rehabilitation (pp. 267290). New York, NY: Demos Medical.

    • Search Google Scholar
    • Export Citation
  • Winstein, C.J., Wolf, S.L., Dromerick, A.W., Lane, C.J., Nelsen, M.A., Lewthwaite, R., … Azen, S.P. (2016). Effect of a task-oriented rehabilitation program on upper extremity recovery following motor stroke: The ICARE Randomized Clinical Trial. The Journal of the American Medical Association 315(6), 571581. doi:10.1001/jama.2016.0276

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wolf, S.L., Winstein, C.J., Miller, J.P., Taub, E., Uswatte, G., Morris, D., … Nichols-Larsen, D. (2006). Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke: The EXCITE randomized clinical trial. The Journal of the American Medical Association, 296, 20952104. doi:10.1001/jama.296.17.2095

    • Crossref
    • Search Google Scholar
    • Export Citation
  • World Health Organization. (2001). International classification of functioning, disability, and health. Geneva, Switzerland: World Health Organization.

    • Search Google Scholar
    • Export Citation
  • Wulf, G. (2007). Self-controlled practice enhances motor learning: Implications for physiotherapy. Physiotherapy 93(2), 96101. doi:10.1016/j.physio.2006.08.005

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wulf, G., & Lewthwaite, R. (2016). Optimizing performance through intrinsic motivation and attention for learning: The OPTIMAL theory of motor learning. Psychonomic Bulletin & Review, 23(5), 13821414. doi:10.3758/s13423-015-0999-9

    • Crossref
    • Search Google Scholar
    • Export Citation
  • Wulf, G., Lewthwaite, R., Cardozo, P., & Chiviacowsky, S. (2017). Triple play: Additive contributions of enhanced expectancies, autonomy support, and external attentional focus to motor learning. The Quarterly Journal of Experimental Psychology, 19. doi:10.1080/17470218.2016.1276204

    • Search Google Scholar
    • Export Citation
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