title: SCISSOR-Spinal Cord Injury Study on Small molecule-derived Rho inhibition: a clinical study protocol.
abstract: The approved analgesic and anti-inflammatory drugs ibuprofen and indometacin block the small GTPase RhoA, a key enzyme that impedes axonal sprouting after axonal damage. Inhibition of the Rho pathway in a central nervous system-effective manner requires higher dosages compared with orthodox cyclooxygenase-blocking effects. Preclinical studies on spinal cord injury (SCI) imply improved motor recovery after ibuprofen/indometacin-mediated Rho inhibition. This has been reassessed by a meta-analysis of the underlying experimental evidence, which indicates an overall effect size of 20.2% regarding motor outcome achieved after ibuprofen/indometacin treatment compared with vehicle controls. In addition, ibuprofen/indometacin may also limit sickness behaviour, non-neurogenic systemic inflammatory response syndrome (SIRS), neuropathic pain and heterotopic ossifications after SCI. Consequently, 'small molecule'-mediated Rho inhibition after acute SCI warrants clinical investigation.
  
  
  
  Protocol of an investigator-initiated clinical open-label pilot trial on high-dose ibuprofen treatment after acute traumatic, motor-complete SCI. A sample of n=12 patients will be enrolled in two cohorts treated with 2400 mg/day ibuprofen for 4 or 12 weeks, respectively. The primary safety end point is an occurrence of serious adverse events, primarily gastroduodenal bleedings. Secondary end points are pharmacokinetics, feasibility and preliminary effects on neurological recovery, neuropathic pain and heterotopic ossifications. The primary safety analysis is based on the incidence of severe gastrointestinal bleedings. Additional analyses will be mainly descriptive and casuistic.
  
  
  
  The clinical trial protocol was approved by the responsible German state Ethics Board, and the Federal Institute for Drugs and Medical Devices. The study complies with the Declaration of Helsinki, the principles of Good Clinical Practice and all further applicable regulations. This safety and pharmacokinetics trial informs the planning of a subsequent randomised controlled trial. Regardless of the result of the primary and secondary outcome assessments, the clinical trial will be reported as a publication in a peer-reviewed journal.
  
  
  
  NCT02096913; Pre-results.
authors.affiliation: Department of Neurology and Experimental Neurology, Spinal Cord Injury Research, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Marcel A
authors.initials: MA
authors.lastname: Kopp
authors.affiliation: Treatment Centre for Spinal Cord Injury, Trauma Hospital Berlin, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Liebscher
authors.affiliation: Department of Neurology and Experimental Neurology, Spinal Cord Injury Research, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Watzlawick
authors.affiliation: Department of Clinical Epidemiology and Applied Biostatistics, Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Martus
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Laufer
authors.affiliation: Department of Neurology and Experimental Neurology, Spinal Cord Injury Research, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Blex
authors.affiliation: Division of Nephrology and Intensive Care, Department of Internal Medicine, Campus Virchow-Klinikum, Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Schindler
authors.affiliation: Department of Neurology, Jüdisches Krankenhaus Berlin, Berlin, Germany Department of Neurology and Experimental Neurology, Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Gerhard J
authors.initials: GJ
authors.lastname: Jungehulsing
authors.affiliation: Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Knüppel
authors.affiliation: Treatment Centre for Spinal Cord Injury, Trauma Hospital Berlin, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Kreutzträger
authors.affiliation: Trauma Surgery and Orthopedics Clinic, Trauma Hospital Berlin, Berlin, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Ekkernkamp
authors.affiliation: Department of Neurology and Experimental Neurology, Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dirnagl
authors.affiliation: Department of Neurology, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Strittmatter
authors.affiliation: Treatment Centre for Spinal Cord Injury, Trauma Hospital Berlin, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Niedeggen
authors.affiliation: Department of Neurology and Experimental Neurology, Spinal Cord Injury Research, Charité-Universitätsmedizin Berlin, Berlin, Germany Treatment Centre for Spinal Cord Injury, Trauma Hospital Berlin, Berlin, Germany Department of Neurology, Spinal Cord Injury Division, The Ohio State University, Wexner Medical Center, Columbus, USA Department of Neuroscience and Center for Brain and Spinal Cord Repair, Department of Physical Medicine and Rehabilitation, The Neurological Institute, The Ohio State University, Wexner Medical Center, Columbus, USA.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Schwab
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000209:etiology; D006801:Humans; D007052:Ibuprofen / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009437:Neuralgia / Q000517:prevention & control; D009999:Ossification, Heterotopic / Q000517:prevention & control; D013119:Spinal Cord Injuries / Q000188:drug therapy*; D018746:Systemic Inflammatory Response Syndrome / Q000517:prevention & control; D055815:Young Adult; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D020742:rhoA GTP-Binding Protein; D007052:Ibuprofen
keywords: Heterotopic ossifications; Neuropathic pain; Neuroprotection; Plasticity; ibuprofen