Top

Published in:

Open Access 01-12-2022 | Shockwave Therapy | Study protocol

The effect of extracorporeal shock wave therapy in acute traumatic spinal cord injury on motor and sensory function within 6 months post-injury: a study protocol for a two-arm three-stage adaptive, prospective, multi-center, randomized, blinded, placebo-controlled clinical trial

Authors: Iris Leister, Rainer Mittermayr, Georg Mattiassich, Ludwig Aigner, Thomas Haider, Lukas Machegger, Harald Kindermann, Anja Grazer-Horacek, Johannes Holfeld, Wolfgang Schaden

Published in: Trials | Issue 1/2022

Abstract

Background

The pathological mechanism in acute spinal cord injury (SCI) is dual sequential: the primary mechanical lesion and the secondary injury due to a cascade of biochemical and pathological changes initiated by the primary lesion. Therapeutic approaches have focused on modulating the mechanisms of secondary injury. Despite extensive efforts in the treatment of SCI, there is yet no causal, curative treatment approach available.

Extracorporeal shock wave therapy (ESWT) has been successfully implemented in clinical use. Biological responses to therapeutic shock waves include altered metabolic activity of various cell types due to direct and indirect mechanotransduction leading to improved migration, proliferation, chemotaxis, modulation of the inflammatory response, angiogenesis, and neovascularization, thus inducing rather a regeneration than repair.

The aim of this clinical study is to investigate the effect of ESWT in humans within the first 48 h after an acute traumatic SCI, with the objective to intervene in the secondary injury phase in order to reduce the extent of neuronal loss.

Methods

This two-arm three-stage adaptive, prospective, multi-center, randomized, blinded, placebo-controlled study has been initiated in July 2020, and a total of 82 patients with acute traumatic SCI will be recruited for the first stage in 15 participating hospitals as part of a two-armed three-stage adaptive trial design. The focused ESWT (energy flux density: 0.1–0.19 mJ/mm², frequency: 2–5 Hz) is applied once at the level of the lesion, five segments above/below, and on the plantar surface of both feet within the first 48 h after trauma.

The degree of improvement in motor and sensory function after 6 months post-injury is the primary endpoint of the study. Secondary endpoints include routine blood chemistry parameters, the degree of spasticity, the ability to walk, urological function, quality of life, and the independence in everyday life.

Discussion

The application of ESWT activates the nervous tissue regeneration involving a multitude of various biochemical and cellular events and leads to a decreased neuronal loss. ESWT might contribute to an improvement in the treatment of acute traumatic SCI in future clinical use.

Trial registration

ClinicalTrials.gov NCT04474106

Available only for authorised users

Chan CWL, Eng JJ, Tator CH, Krassioukov A. Epidemiology of sport-related spinal cord injuries: a systematic review. J Spinal Cord Med. 2016;39(3):255–64. https://doi.org/10.1080/10790268.2016.1138601.CrossRefPubMedPubMedCentral

Lee BB, Cripps RA, Fitzharris M, Wing PC. The global map for traumatic spinal cord injury epidemiology: update 2011, global incidence rate. Spinal Cord. 2014;52(2):110–6. https://doi.org/10.1038/sc.2012.158.CrossRefPubMed

Chen Y, He Y, DeVivo MJ. Changing demographics and injury profile of new traumatic spinal cord injuries in the United States, 1972–2014. Arch Phys Med Rehabil. 2016;97(10):1610–9. https://doi.org/10.1016/j.apmr.2016.03.017.CrossRefPubMed

Wyndaele M, Wyndaele JJ. Incidence, prevalence and epidemiology of spinal cord injury: what learns a worldwide literature survey? Spinal Cord. 2006;44(9):523–9. https://doi.org/10.1038/sj.sc.3101893.CrossRefPubMed

World Health Organization. International perspectives on spinal cord injury. 2003.

Patel SA, Vaccaro AR, Rihn JA. Epidemiology of spinal injuries in sports. Oper Tech Sports Med. 2013;21(3):146–51. https://doi.org/10.1053/j.otsm.2013.10.003.CrossRef

Carll KE, Park AE, Tortolani PJ. Epidemiology of catastrophic spine injuries in high school, college, and professional sports. Semin Spine Surg. 2010;22(4):168–72. https://doi.org/10.1053/j.semss.2010.06.007.CrossRef

MJ DV. Epidemiology of traumatic spinal cord injury: trends and future implications. Spinal Cord. 2012;50(5):365–72 Available from: http://www.nature.com/articles/sc2011178. [cited 2018 Dec 8].CrossRef

Mattiassich G, Gollwitzer M, Gaderer F, Blocher M, Osti M, Lill M, et al. Functional outcomes in individuals undergoing very early (< 5 h) and early (5–24 h) surgical decompression in traumatic cervical spinal cord injury: analysis of neurological improvement from the Austrian Spinal Cord Injury Study. J Neurotrauma. 2017;34(24):3362–71. https://doi.org/10.1089/neu.2017.5132.CrossRefPubMed

10.

Silva NA, Sousa N, Reis RL, Salgado AJ. From basics to clinical: a comprehensive review on spinal cord injury. Prog Neurobiol. 2014;114:25–57. https://doi.org/10.1016/j.pneurobio.2013.11.002.CrossRefPubMed

11.

Fehlings MG, Perrin RG. The role and timing of early decompression for cervical spinal cord injury: update with a review of recent clinical evidence. Injury. 2005;36(SUPPL. 2):13–26. https://doi.org/10.1016/j.injury.2005.06.011.CrossRef

12.

Hausner T, Nógrádi A. The use of shock waves in peripheral nerve regeneration: new perspectives? Int Rev Neurobiol. 2013;109:85–98. https://doi.org/10.1016/B978-0-12-420045-6.00003-1.CrossRefPubMed

13.

Buss A, Pech K, Merkler D, Kakulas BA, Martin D, Schoenen J, et al. Sequential loss of myelin proteins during Wallerian degeneration in the human spinal cord. Brain. 2005;128(2):356–64. https://doi.org/10.1093/brain/awh355.CrossRefPubMed

14.

Zhang Z, Guth L. Experimental spinal cord injury: Wallerian degeneration in the dorsal column is followed by revascularization, glial proliferation, and nerve regeneration. Exp Neurol. 1997;147(1):159–71. https://doi.org/10.1006/exnr.1997.6590.CrossRefPubMed

15.

Gwak YS, Hulsebosch CE. Neuronal hyperexcitability: a substrate for central neuropathic pain after spinal cord injury. Curr Pain Headache Rep. 2011;15(3):215–22. https://doi.org/10.1007/s11916-011-0186-2.CrossRefPubMed

16.

Hains BC, Willis WD, Hulsebosch CE. Temporal plasticity of dorsal horn somatosensory neurons after acute and chronic spinal cord hemisection in rat. Brain Res. 2003;970(1–2):238–41. https://doi.org/10.1016/S0006-8993(03)02347-3.CrossRefPubMed

17.

Mittermayr R, Antonic V, Hartinger J, Kaufmann H, Redl H, Téot L, et al. Extracorporeal shock wave therapy (ESWT) for wound healing: technology, mechanisms, and clinical efficacy. Wound Repair Regen. 2012;20(4):456–465. https://doi.org/10.1111/j.1524-475X.2012.00796e.x. [cited 2018 Apr 8]

18.

Iskratsch T, Wolfenson H, Sheetz MP. Appreciating force and shape — the rise of mechanotransduction in cell biology. Nat Rev Mol Cell Biol. 2014;15(12):825–33 Available from: http://www.nature.com/doifinder/10.1038/nrm3903.CrossRef

19.

Schaden W, Mittermayr R, Haffner N, Smolen D, Gerdesmeyer L, Wang CJ. Extracorporeal shockwave therapy (ESWT) - first choice treatment of fracture non-unions? Int J Surg. 2015;24:179–83. https://doi.org/10.1016/j.ijsu.2015.10.003 Pt B.CrossRefPubMed

20.

Pastor D, Valera H, Olmo JA, Estirado A, Martínez S. Shock wave and mesenchymal stem cells as treatment in the acute phase of spinal cord injury: a pilot study. Rehabilitacion. 2021; Available from: https://pubmed.ncbi.nlm.nih.gov/33966896/. [cited 2021 Aug 13].

21.

D’Agostino MC, Craig K, Tibalt E, Respizzi S. Shock wave as biological therapeutic tool: from mechanical stimulation to recovery and healing, through mechanotransduction. Int J Surg. 2015;24:147–53. https://doi.org/10.1016/j.ijsu.2015.11.030 Pt B.CrossRefPubMed

22.

AG SM. STORZ MEDICAL’s NEUROLITH® receives CE approval – Transcranial Pulse Stimulation (TPS) on the central nervous system of patients with Alzheimer’s disease. 2019 [cited 2019 Jan 26]. Available from: https://www.storzmedical.com/news-press/entry/neurolith-ce-approval-transcranial-pulse-stimulation-tps-treatment-alzheimer-disease.html

23.

Hausner T, Pajer K, Halat G, Hopf R, Schmidhammer R, Redl H, et al. Improved rate of peripheral nerve regeneration induced by extracorporeal shock wave treatment in the rat. Exp Neurol. 2012;236(2):363–70. https://doi.org/10.1016/j.expneurol.2012.04.019.CrossRefPubMed

24.

Lobenwein D, Tepeköylü C, Kozaryn R, Pechriggl EJ, Bitsche M, Graber M, et al. Shock wave treatment protects from neuronal degeneration via a Toll-like receptor 3 dependent mechanism: implications of a first-ever causal treatment for ischemic spinal cord injury. J Am Heart Assoc. 2015:1–13 Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845137/pdf/JAH3-4-e002440.pdf. [cited 2018 Mar 8].

25.

Yamaya S, Ozawa H, Kanno H, Kishimoto KN, Sekiguchi A, Tateda S, et al. Low-energy extracorporeal shock wave therapy promotes vascular endothelial growth factor expression and improves locomotor recovery after spinal cord injury. J Neurosurg. 2014;121(6):1514–1525. https://doi.org/10.3171/2014.8.JNS132562. [cited 2018 Mar 9]

26.

Yahata K, Kanno H, Ozawa H, Yamaya S, Tateda S, Ito K, et al. Low-energy extracorporeal shock wave therapy for promotion of vascular endothelial growth factor expression and angiogenesis and improvement of locomotor and sensory functions after spinal cord injury. J Neurosurg Spine. 2016;25(6):745–55. https://doi.org/10.3171/2016.4.SPINE15923.CrossRefPubMed

27.

Matsuda M, Kanno H, Sugaya T, Yamaya S, Yahata K, Handa K, et al. Low-energy extracorporeal shock wave therapy promotes BDNF expression and improves functional recovery after spinal cord injury in rats. Exp Neurol. 2020;328 Available from: https://pubmed.ncbi.nlm.nih.gov/32087252/. [cited 2021 Aug 13].

28.

Lohse-Busch H, Reime U, Falland R. Symptomatic treatment of unresponsive wakefulness syndrome with transcranially focused extracorporeal shock waves. NeuroRehabilitation. 2014;35(2):235–44. https://doi.org/10.3233/NRE-141115.CrossRefPubMed

29.

Davis T, Stojadinovic A, Anam K, Amare M, Naik S, Peoples G, et al. Extracorporeal shock wave therapy suppresses the early proinflammatory immune response to a severe cutaneous burn injury. Int Wound J. 2009;6:11–21 Available from: http://ovidsp.ovid.com/ovidweb.cgi?T = JS%7B&%7DPAGE = reference%7B&%7DD = emed9%7B&%7DNEWS=N%7B&%7DAN = 2009120408.CrossRef

30.

Holfeld J, Tepeköylü C, Kozaryn R, Urbschat A, Zacharowski K, Grimm M, et al. Shockwave therapy differentially stimulates endothelial cells: implications on the control of inflammation via Toll-like receptor 3. Inflammation. 2013;37(1):65–70. https://doi.org/10.1007/s10753-013-9712-1.CrossRef

31.

Sukubo NG, Respizzi S, Locati M, Tibalt E, D’Agostino MC. Effect of shock waves on macrophages: a possible role in tissue regeneration and remodeling. Int J Surg. 2015:124–30. https://doi.org/10.1016/j.ijsu.2015.07.719.

32.

Holfeld J, Tepeköylü C, Reissig C, Lobenwein D, Scheller B, Kirchmair E, et al. Toll-like receptor 3 signalling mediates angiogenic response upon shock wave treatment of ischaemic muscle. Cardiovasc Res. 2016;109(2):331–43. https://doi.org/10.1093/cvr/cvv272 [cited 2019 Mar 12].CrossRefPubMed

33.

Holfeld J, Tepeköylü C, Blunder S, Lobenwein D, Kirchmair E, Dietl M, et al. Low energy shock wave therapy induces angiogenesis in acute hind-limb ischemia via VEGF receptor 2 phosphorylation. PLoS One. 2014;9(8):1–7. https://doi.org/10.1371/journal.pone.0103982.CrossRef

34.

Mirea A, Onose G, Padure L, Rosulescu E. Extracorporeal shockwave therapy (ESWT) benefits in spastic children with cerebral palsy (CP). J Med Life. 2014;7(3):127–32 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25870710%5Cnhttp://www.pubmedcentral.nih.gov/articlerender.fcgi?artid = PMC4391398.PubMedPubMedCentral

35.

Brouwers E, Van De Meent H, Curt A, Starremans B, Hosman A, Bartels R. Definitions of traumatic conus medullaris and cauda equina syndrome: a systematic literature review. Spinal Cord. 2017;55(10):886–90. https://doi.org/10.1038/sc.2017.54.CrossRefPubMed

36.

Bracken M. Steroids for acute spinal cord injury. Cochrane Database Syst Rev. 2012;1:CD001046. https://doi.org/10.1002/14651858.CD001046.pub2.CrossRefPubMed

37.

Chmelizek F, Jonas HP, Kathrein A, Knop C. Hochdosiertes Methylprednisolon beim spinalen Trauma - Konsensus Stetement. Int Zeitung für ärztliche Fortbildung. 2006;16(2):1–8.

38.

Hurlbert RJ. Methylprednisolone for acute spinal cord injury: an inappropriate standard of care. J Neurosurg Spine. 2000;168(9):1–7 Available from: http://thejns.org/doi/abs/10.3171/spi.2000.93.1.0001%0Ahttps://thejns.org/view/journals/j-neurosurg-spine/93/1/article-p1.xml.CrossRef

39.

Chen A, Xu XM, Kleitman N, Bunge MB. Methylprednisolone administration improves axonal regeneration into Schwann cell grafts in transected adult rat thoracic spinal cord. Exp Neurol. 1996;138(2):261–76. https://doi.org/10.1006/exnr.1996.0065.CrossRefPubMed

40.

American Spinal Injury Association. International standards for neurological classification of SCI (ISNCSCI) Exam, vol. 99; 2002. p. 4–5.

41.

American Spinal Injury Association. International standards for the classification of spinal cord injury: motor exam guide. 2008;(June):1–16.

42.

American Spinal Injury Association. International standards for the classification of spinal cord injury: key sensory points. 2009;(June):1–6. Available from: papers2://publication/uuid/738676A2-C12D-46C0-A122-7A34A766144E

43.

Högel F, Vastmans J, Vogel M, Bühren V. Verletzungen des Rückenmarks – Akutbehandlung. Orthop Unfallchirurgie up2date. 2016;11(06):451–479. https://doi.org/10.1055/s-0042-101455

44.

Hsieh JTC, Wolfe DL, Miller WC, Curt A, SCIRE Research Team. Spasticity outcome measures in spinal cord injury: psychometric properties and clinical utility. Spinal Cord. 2008;46(2):86–95 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17909559.CrossRef

45.

Hornby TG, Rymer WZ, Benz EN, Schmit BD. Windup of flexion reflexes in chronic human spinal cord injury: a marker for neuronal plateau potentials? J Neurophysiol. 2003;89(1):416–426. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12522190, [cited 2019 Sep 18]

46.

Adams MM, Ginis KAM, Hicks AL. The spinal cord injury spasticity evaluation tool: development and evaluation. Arch Phys Med Rehabil. 2007;88(9):1185–92 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17826466. [cited 2019 Sep 18].CrossRef

47.

Bohannon RW, Smith MB. Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther. 1987;67(2):206–7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/3809245. [cited 2018 Apr 8].CrossRef

48.

Steeves JD, Lammertse D, Curt A, Fawcett JW, Tuszynski MH, Ditunno JF, et al. Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial outcome measures. Spinal Cord. 2007;45(3):206–21. https://doi.org/10.1038/sj.sc.3102008.CrossRefPubMed

49.

Pandyan AD, Johnson GR, Price CI, Curless RH, Barnes MP, Rodgers H. A review of the properties and limitations of the Ashworth and modified Ashworth Scales as measures of spasticity. Clin Rehabil. 1999;13(5):373–383. https://doi.org/10.1191/026921599677595404. [cited 2019 Sep 18]

50.

Craven BC, Morris AR. Modified Ashworth scale reliability for measurement of lower extremity spasticity among patients with SCI. Spinal Cord. 2010;48(3):207–13 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19786977. [cited 2019 Sep 18].CrossRef

51.

Haas BM, Bergström E, Jamous A, Bennie A. The inter rater reliability of the original and of the modified Ashworth scale for the assessment of spasticity in patients with spinal cord injury. Spinal Cord. 1996;34(9):560–4 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8883191. [cited 2019 Sep 18].CrossRef

52.

Tederko P, Krasuski M, Czech J, Dargiel A, Garwacka-Jodzis I, Wojciechowska A. Reliability of clinical spasticity measurements in patients with cervical spinal cord injury. Ortop Traumatol Rehabil. 9(5):467–83 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18026067. [cited 2019 Sep 18].

53.

Lechner HE, Frotzler A, Eser P. Relationship between self- and clinically rated spasticity in spinal cord injury. Arch Phys Med Rehabil. 2006;87(1):15–9 Available from: https://linkinghub.elsevier.com/retrieve/pii/S0003999305011408. [cited 2019 Sep 18].CrossRef

54.

VAB S, Becher JG, Beelen A, Lankhorst GJ. Clinical assessment of spasticity in children with cerebral palsy: a critical review of available instruments. Dev Med Child Neurol. 2006;48(1):64–73. https://doi.org/10.1017/S0012162206000132 [cited 2019 Sep 18].CrossRef

55.

da Silva LT. Nine-hole peg test for evaluation of hand function: the advantages and shortcomings. Neurol India. 2017;65(5):1033. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28879892. [cited 2018 Dec 20]

56.

Mulcahey MJ, Smith BT, Betz RR. Psychometric rigor of the Grasp and Release Test for measuring functional limitation of persons with tetraplegia: a preliminary analysis. J Spinal Cord Med. 2004;27(1):41–46. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15156936. [cited 2018 Dec 20]

57.

Schnake KJ, Schroeder GD, Vaccaro AR, Oner C. AOSpine classification systems (subaxial, thoracolumbar). J Orthop Trauma. 2017;31(9):S14–23. https://doi.org/10.1097/BOT.0000000000000947.CrossRefPubMed

58.

AOSpine Research Team. AOSpine subaxial classification system. 2018. Available from: www.aospine.org/classification

59.

AOSpine Research Team. AOSpine thoracolumbar classification system. 2018. Available from: http://www.spinesurgery.de/images/aerzte/klassifikationen/bws-lws/AOSpine_Thoracolumbar_Classification_System_pocket_card.pdf

60.

You JY, Lee JW, Lee E, Lee GY, Yeom JS, Kang HS. MR classification system based on axial images for cervical compressive myelopathy. Radiology. 2015;276(2):553–61. https://doi.org/10.1148/radiol.2015142384.CrossRefPubMed

61.

Machino M, Yukawa Y, Ito K, Kanbara S, Morita D, Kato F. Posterior ligamentous complex injuries are related to fracture severity and neurological damage in patients with acute thoracic and lumbar burst fractures. Yonsei Med J. 2013;54(4):1020–5. https://doi.org/10.3349/ymj.2013.54.4.1020.CrossRefPubMedPubMedCentral

62.

Vaccaro AR, Rihn JA, Saravanja D, Anderson DG, Hilibrand AS, Albert TJ, et al. Injury of the posterior ligamentous complex of the thoracolumbar spine: a prospective evaluation of the diagnostic accuracy of magnetic resonance imaging. Spine (Phila Pa 1976). 2009;34(23):841–7. https://doi.org/10.1097/BRS.0b013e3181bd11be.CrossRef

63.

Rihn JA, Fisher C, Harrop J, Morrison W, Yang N, Vaccaro AR. Assessment of the posterior ligamentous complex following acute cervical spine trauma. J Bone Jt Surg Ser A. 2010;92(3):583–9. https://doi.org/10.2106/JBJS.H.01596.CrossRef

64.

Schulz KF, Grimes DA. Blinding in randomised trials: hiding who got what. Lancet. 2002;359(9307):696–700. https://doi.org/10.1016/S0140-6736(02)07816-9.CrossRefPubMed

65.

Whitehead J. The design and analysis of sequential clinical trials: John Wiley & Sons; 1997.CrossRef

66.

Thomas DR, Zumbo BD. Difference scores from the point of view of reliability and repeated-measures ANOVA: in defense of difference scores for data analysis, vol. 72. Los Angeles: Educational and Psychological Measurement. SAGE PublicationsSage CA; 2012. p. 37–43. https://doi.org/10.1177/0013164411409929. [cited 2021 Oct 19]CrossRef

67.

Dalecki M, Willits FK. Examining change using regression analysis: three approaches compared. Sociol Spectr. 1991;11(2):127–45. https://doi.org/10.1080/02732173.1991.9981960.CrossRef

68.

Fehlings MG, Vaccaro A, Wilson JR, Singh A, Cadotte DW, Harrop JS, et al. Early versus delayed decompression for traumatic cervical spinal cord injury: results of the surgical timing in acute spinal cord injury study (STASCIS). PLoS One. 2012;7(2):1–8. https://doi.org/10.1371/journal.pone.0032037.CrossRef

69.

Elster EA, Stojadinovic A, Forsberg J, Shawen S, Andersen RC, Schaden W. Extracorporeal shock wave therapy for nonunion of the tibia. J Orthop Trauma. 2010;24(3):133–41. https://doi.org/10.1097/BOT.0b013e3181b26470.CrossRefPubMed

Title: The effect of extracorporeal shock wave therapy in acute traumatic spinal cord injury on motor and sensory function within 6 months post-injury: a study protocol for a two-arm three-stage adaptive, prospective, multi-center, randomized, blinded, placebo-controlled clinical trial
Authors: Iris Leister
Rainer Mittermayr
Georg Mattiassich
Ludwig Aigner
Thomas Haider
Lukas Machegger
Harald Kindermann
Anja Grazer-Horacek
Johannes Holfeld
Wolfgang Schaden
Publication date: 01-12-2022
Publisher: BioMed Central
Keyword: Shockwave Therapy
Published in: Trials / Issue 1/2022
Electronic ISSN: 1745-6215
DOI: https://doi.org/10.1186/s13063-022-06161-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

The effect of extracorporeal shock wave therapy in acute traumatic spinal cord injury on motor and sensory function within 6 months post-injury: a study protocol for a two-arm three-stage adaptive, prospective, multi-center, randomized, blinded, placebo-controlled clinical trial

Abstract

Background

Methods

Discussion

Trial registration

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Discussion

Trial registration

Please log in to get access to this content

Other articles of this Issue 1/2022

Virtual Arm Boot Camp (V-ABC): study protocol for a mixed-methods study to increase upper limb recovery after stroke with an intensive program coupled with a grasp count device

Transmyringeal ventilation tube insertion for unilateral Menière’s disease: a protocol for a prospective, sham-controlled, double-blinded, randomized, clinical trial

Quality problems of clinical trials in China: evidence from quality related studies

Effectiveness of rib fixation compared to pain medication alone on pain control in patients with uncomplicated rib fractures: study protocol of a pragmatic multicenter randomized controlled trial—the PAROS study (Pain After Rib OSteosynthesis)

Improving adherence to acute low back pain guideline recommendations with chiropractors and physiotherapists: the ALIGN cluster randomised controlled trial

Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial