Transcranial Near-Infrared Laser Therapy for Stroke: How to Recover from Futility in the NEST-3 Clinical Trial
Development of drugs and devices for the treatment of stroke is not exempt from current translational research standards, which include Stroke Treatment Academic Industry Roundtable (STAIR) criteria and RIGOR guidelines. Near-infrared laser therapy (NILT) was developed to treat stroke in an era when STAIR criteria were not adhered to, thus NILT was not optimized in multiple species, nor was it optimized for efficacy across barriers in translational animal models before proceeding to expensive and extensive clinical trials. Moreover, the majority of rodent studies did not adhere to RIGOR guidelines. This ultimately led to failure in the NeuroThera Effectiveness and Safety Trial-3. Because NILT remains a promising therapeutic approach to treat stroke, we designed a systematic study to determine laser light penetration profiles across the skull of four different species with increasing skull thickness: mouse, rat, rabbit, and human.
Our study demonstrates that NILT differentially penetrates the skulls. There is especially extensive attenuation of light energy penetration across the human calvaria, compared with animal skulls, which suggests that the power density setting used in stroke clinical trials may not have optimally stimulated neuroprotection and repair pathways. The results of our study suggest that NILT cannot be sufficiently optimized in “small” animals and directly translated to humans because of significant variances of skull thickness and penetration characteristics across species. NILT neuroprotection should be further studied using a research design that endeavors to incorporate human skull characteristics (thickness) into the development plan to increase the probability of success in stroke victims.
KeywordsAcute ischemic stroke Alzheimer’s disease Amyloid Behavior Laser therapy Mitochondria Neuroprotection NEST trials NILT Parkinson’s disease Translational science Traumatic brain injury Toxicity Victim Unmet clinical need
Conflict of Interest Statement
This study utilized a K-Laser model K-1200 device. K-Laser, Inc. did not have an editorial influence on the study design or scientific content of this article.
Disclosures and Acknowledgments
Dr. Lapchak serves as editor-in-chief of the Journal of Neurology & Neurophysiology and associate editor of Translational Stroke Research. The scientific content of this work was not directly supported by the National Institutes of Health or any other funding source external to Cedars-Sinai Medical Center. He was supported in part by a U01 translational research grant NS060685. Paul D. Boitano has no disclosures.
- 4.Desmet KD, Paz DA, Corry JJ, Eells JT, Wong-Riley MT, Henry MM, Buchmann EV, Connelly MP, Dovi JV, Liang HL, Henshel DS, Yeager RL, Millsap DS, Lim J, Gould LJ, Das R, Jett M, Hodgson BD, Margolis D, Whelan HT (2006) Clinical and experimental applications of NIR-LED photobiomodulation. Photomed Laser Surg 24:121–128CrossRefPubMedGoogle Scholar
- 9.Hacke W, Schellinger PD, Albers GW, Bornstein NM, Dahlof BL, Fulton R, Kasner SE, Shuaib A, Richieri SP, Dilly SG, Zivin J, Lees KR; NEST 3 Committees and Investigators (2014) Transcranial laser therapy in acute stroke treatment: results of neurothera effectiveness and safety trial 3, a phase III clinical end point device trial. Stroke 45:3187–3193Google Scholar
- 12.Lampl Y, Zivin JA, Fisher M, Lew R, Welin L, Dahlof B, Borenstein P, Andersson B, Perez J, Caparo C, Ilic S, Oron U (2007) Infrared laser therapy for ischemic stroke: a new treatment strategy: results of the NeuroThera Effectiveness and Safety Trial-1 (NEST-1). Stroke 38:1843–1849CrossRefPubMedGoogle Scholar
- 13.Landis SC, Amara SG, Asadullah K, Austin CP, Blumenstein R, Bradley EW, Crystal RG, Darnell RB, Ferrante RJ, Fillit H, Finkelstein R, Fisher M, Gendelman HE, Golub RM, Goudreau JL, Gross RA, Gubitz AK, Hesterlee SE, Howells DW, Huguenard J, Kelner K, Koroshetz W, Krainc D, Lazic SE, Levine MS, Macleod MR, McCall JM, Moxley RT 3rd, Narasimhan K, Noble LJ, Perrin S, Porter JD, Steward O, Unger E, Utz U, Silberberg SD (2012) A call for transparent reporting to optimize the predictive value of preclinical research. Nature 490:187–191PubMedCentralCrossRefPubMedGoogle Scholar
- 27.Lyden P, Lu M, Jackson C, Marler J, Kothari R, Brott T, Zivin J, The National Institute of Neurological Disorders and Stroke rt PASSG (1999) Underlying structure of the National Institutes of Health Stroke Scale: results of a factor analysis. Stroke 30:2347Google Scholar
- 36.Voie A, Dirnbacher M, Fisher D, Holscher T (2014). Parametric mapping and quantitative analysis of the human calvarium. Computerized medical imaging and graphics: the official journal of the Computerized Medical Imaging Society. 38(8):675–682. doi: 10.1016/j.compmedimag.2014.06.022. pmid:25069430.Google Scholar
- 39.Zivin JA, Albers GW, Bornstein N, Chippendale T, Dahlof B, Devlin T, Fisher M, Hacke W, Holt W, Ilic S, Kasner S, Lew R, Nash M, Perez J, Rymer M, Schellinger P, Schneider D, Schwab S, Veltkamp R, Walker M, Streeter J (2009) Effectiveness and safety of transcranial laser therapy for acute ischemic stroke. Stroke 40:1359–1364Google Scholar