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For Peer Review Only - Page 1 of 33 BMJ Open BMJ Open BMJ Open: first published as 10.1136/bmjopen-2015-010651 on 26 July 2016. Downloaded from SCISSOR – Spinal Cord Injury Study on Small molecule derived Rho-inhibition: A Clinical Study Protocol ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2015-010651 Article Type: Protocol Date Submitted by the Author: 23-Nov-2015 Complete List of Authors: Kopp, Marcel; Charité Universitätsmedizin Berlin, Department of Neurology & Experimental Neurology, Spinal Cord Injury Research Liebscher, Thomas; Trauma Hospital Berlin, Treatment Centre for Spinal Cord Injury Watzlawick, Ralf; Charité Universitätsmedizin Berlin, Department of Neurology & Experimental Neurology, Spinal Cord Injury Research Martus, Peter; Department of Clinical Epidemiology and Applied Biostatistics, Eberhard Karls Universität Tübingen Laufer, Stefan; Eberhard-Karls-University Tübingen, Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy Blex, Christian; Charité Universitätsmedizin Berlin, Department of Neurology & Experimental Neurology, Spinal Cord Injury Research Schindler, Ralf; Charité-University Medicine Berlin, Division of Nephrology and Intensive Care, Department of Internal Medicine, Campus Virchow- Klinikum http://bmjopen.bmj.com/ Jungehulsing, Gerhard; Jüdisches Krankenhaus Berlin, Department of Neurology Knüppel, Sven; German Institute of Human Nutrition Potsdam-Rehbrücke, Department of Epidemiology Kreutzträger, Martin; Trauma Hospital Berlin, Treatment Centre for Spinal Cord Injury Ekkernkamp, Axel ; Trauma Hospital Berlin, Trauma Surgery and Orthopedics Clinic Dirnagl, Ulrich; Charité Universitätsmedizin Berlin, Department of on October 2, 2021 by guest. Protected copyright. Neurology & Experimental Neurology Strittmatter, Stephen; Yale University School of Medicine, Program in Cellular Neuroscience, Neurodegeneration and Repair, and Department of Neurology Niedeggen, Andreas; Trauma Hospital Berlin, Treatment Centre for Spinal Cord Injury Schwab, Jan; Charité Berlin, Department of Neurology & Experimental Neurology, Spinal Cord Injury Research; Department of Neurology, Spinal Cord Injury Division, The Ohio State University, Wexner Medical Center <b>Primary Subject Neurology Heading</b>: Secondary Subject Heading: Pharmacology and therapeutics, Research methods ibuprofen, Neuroprotection, Plasticity, Neuropathic pain, Heterotopic Keywords: ossifications For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 33 BMJ Open 1 BMJ Open: first published as 10.1136/bmjopen-2015-010651 on 26 July 2016. Downloaded from 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 33 1 BMJ Open: first published as 10.1136/bmjopen-2015-010651 on 26 July 2016. Downloaded from 2 3 Study Protocol 4 5 6 7 SCISSOR – Spinal Cord Injury Study on Small molecule derived Rho-inhibition: A 8 9 Clinical Study Protocol 10 11 12 13 1 2 1 3 4 14 Marcel A. Kopp *, Thomas Liebscher * Ralf Watzlawick *, Peter Martus , Stefan Laufer , 15 ChristianFor Blex1, Ralf peer Schindler5, Gerhard review J. Jungehulsing only6,7, Sven Knüppel7, Axel 16 8 9 10 17 Ekkernkamp , Ulrich Dirnagl , Stephen M. Strittmatter , 18 Andreas Niedeggen2, Jan M. Schwab1,2,11,12 19 20 21 1Department of Neurology and Experimental Neurology, Spinal Cord Injury Research, Charité - 22 Universitätsmedizin Berlin, Germany. 2Treatment Centre for Spinal Cord Injury, Trauma Hospital Berlin, Germany. 23 3 Department of Clinical Epidemiology and Applied Biostatistics, Eberhard Karls Universität Tübingen, Germany 24 4 25 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard-Karls-University 26 Tübingen, Germany. 5 Division of Nephrology and Intensive Care, Department of Internal Medicine, Campus 27 Virchow-Klinikum, Charité-University Medicine Berlin, Berlin, Germany. 6 Jüdisches Krankenhaus Berlin, 28 Department of Neurology, Germany. 7 Department of Epidemiology German Institute of Human Nutrition 29 8 30 Potsdam-Rehbrücke, Germany. Trauma Surgery and Orthopedics Clinic, Trauma Hospital Berlin, Germany. 31 9 Department of Neurology and Experimental Neurology, Center for Stroke Research Berlin, Charité - 32 Universitätsmedizin Berlin, Germany. 10Program in Cellular Neuroscience, Neurodegeneration and Repair, and 33 11 Department of Neurology, Yale University School of Medicine, New Haven, USA. Department of Neurology, 34 http://bmjopen.bmj.com/ 12 35 Spinal Cord Injury Division, The Ohio State University, Wexner Medical Center, Columbus, USA Department of 36 Neuroscience and Center for Brain and Spinal Cord Repair, Department of Physical Medicine and Rehabilitation, 37 The Neuroscience Research Institute, The Ohio State University, Wexner Medical Center, Columbus, USA. 38 39 40 * contributed equally to this work 41 42 on October 2, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 Correspondence 51 Prof. Jan Schwab, MD, PhD 52 Department of Neurology and Experimental Neurology, Spinal Cord Injury Research (Clinical and experimental 53 Neuroparaplegiology) , Charité - Universitätsmedizin Berlin Charitéplatz 1, D-10117 Berlin 54 55 Phone: 0049-30-450-660293 56 Fax: 0049-30-450-560942 57 E-mail: [email protected] 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 1 Page 3 of 33 BMJ Open 1 BMJ Open: first published as 10.1136/bmjopen-2015-010651 on 26 July 2016. Downloaded from 2 3 ABSTRACT 4 5 6 Introduction The approved analgesic and anti-inflammatory drugs ibuprofen and 7 8 indometacin target the COX-pathway unselectively. Moreover, they block the small GTPase 9 RhoA, a key enzyme within a downstream cascade of extra-neuronal signals that impede 10 11 axonal sprouting after axonal damage. Preclinical studies in spinal cord injury (SCI) imply 12 improved motor recovery after ibuprofen/indometacin-mediated Rho-inhibition. This has been 13 14 re-assessed by a meta-analysis of the underlying experimental evidence, which indicates an 15 overall effectFor size of 20.2% peer regarding motorreview outcome achieved only after ibuprofen/indometacin 16 17 treatment compared to vehicle controls. Additionally, anti-inflammatory actions of 18 19 ibuprofen/indometacin probably limit the development of sickness behavior, non-neurogenic 20 systemic inflammatory response syndrome (SIRS), neuropathic pain, and heterotopic 21 22 ossifications after SCI. Consequently, ‘small molecule’ mediated Rho-inhibition after acute 23 SCI warrants clinical investigation. 24 25 Methods and analysis We report the protocol of an investigator initiated clinical pilot trial on 26 high-dose ibuprofen treatment after acute traumatic, motor complete SCI. The open-label 27 28 study has the primary safety endpoint: occurrence of serious adverse events, primarily 29 gastroduodenal bleedings. Secondary endpoints are pharmacokinetics, feasibility and 30 31 preliminary effects on neurological recovery, neuropathic pain and heterotopic ossifications. 32 Underlying experimental evidence was challenged by systematic review of preclinical studies 33 34 on ibuprofen/indometacin effects on motor recovery after SCI. The primary safety analysis is http://bmjopen.bmj.com/ 35 based on the incidence of severe gastrointestinal bleedings. Additional analyses will be 36 37 mainly descriptive and casuistic. 38 Ethics and dissemination The clinical trial protocol was approved by the responsible 39 40 German state Ethics Board, and the Federal Institute for Drugs and Medical Devices. The 41 study complies with the Helsinki Declaration, the principles of Good Clinical Practice and all 42 on October 2, 2021 by guest. Protected copyright. 43 further applicable regulations. The current safety and pharmacokinetics trial informs the 44 45 planning of a subsequent randomized controlled trial. Regardless to the result of the primary 46 and secondary outcome assessments the clinical trial will be reported as publication in a 47 48 peer-reviewed journal. 49 Registration ClinicalTrials.gov identifier: NCT02096913. 50 51 52 53 54 (300 words) 55 56 57 Keywords: ibuprofen, neuroprotection, plasticity, neuropathic pain, heterotopic ossifications 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 2 BMJ Open Page 4 of 33 1 BMJ Open: first published as 10.1136/bmjopen-2015-010651 on 26 July 2016. Downloaded from 2 3 INTRODUCTION 4 5 At present, the effective pharmacological treatment of acute traumatic spinal cord injury 6 (SCI) is an unmet medical need.[1] The current opportunities for restitution of neurological 7 8 function after SCI are limited to early surgical decompression, stabilization, and 9 physiotherapy. Neuroprotective or plasticity enhancing therapies are under investigation in 10 11 preclinical studies and early-phase clinical trials. As yet, however, none of these approaches 12 could be translated into clinical routine.[2-4] 13 14 A major reason for the poor prognosis of central nervous system (CNS) injury is the 15 incapacity ofFor axons to peerre-grow within review the CNS. Molecular only barriers preventing axonal 16 17 regeneration after SCI are situated in the environment of the injured axon i.e. in the scar 18 19 tissue and myelin.[5 6] Those molecules, such as chondroitin sulfate proteoglycans 20 (CSPGs), Nogo-A,
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