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© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Background

IMI2-PainCare-BioPain-RCT3 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics, by providing a quantitative understanding between drug exposure and effects of the drug on nociceptive signal processing in human volunteers. IMI2-PainCare-BioPain-RCT3 will focus on biomarkers derived from non-invasive electroencephalographic (EEG) measures of brain activity.

Methods

This is a multisite single-dose, double-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD) and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from scalp EEG measurements (laser-evoked brain potentials [LEPs], pinprick-evoked brain potentials [PEPs], resting EEG) will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose in separate study periods. Medication effects will be assessed concurrently in a non-sensitized normal condition and a clinically relevant hyperalgesic condition (high-frequency electrical stimulation of the skin). Patient-reported outcomes will also be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split between LEP and PEP under tapentadol. Remaining treatment arm effects on LEP or PEP or effects on EEG are key secondary confirmatory analyses. Complex statistical analyses and PK-PD modeling are exploratory.

Discussion

LEPs and PEPs are brain responses related to the selective activation of thermonociceptors and mechanonociceptors. Their amplitudes are dependent on the responsiveness of these nociceptors and the state of the pathways relaying nociceptive input at the level of the spinal cord and brain. The magnitude of resting EEG oscillations is sensitive to changes in brain network function, and some modulations of oscillation magnitude can relate to perceived pain intensity, variations in vigilance, and attentional states. These oscillations can also be affected by analgesic drugs acting on the central nervous system. For these reasons, IMI2-PainCare-BioPain-RCT3 hypothesizes that EEG-derived measures can serve as biomarkers of target engagement of analgesic drugs for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification.

Trial registration

This trial was registered 25/06/2019 in EudraCT (2019%2D%2D001204-37).

Details

Title
IMI2-PainCare-BioPain-RCT3: a randomized, double-blind, placebo-controlled, crossover, multi-center trial in healthy subjects to investigate the effects of lacosamide, pregabalin, and tapentadol on biomarkers of pain processing observed by electroencephalography (EEG)
Author
Mouraux, André 1   VIAFID ORCID Logo  ; Bloms-Funke, Petra 2 ; Boesl, Irmgard 3 ; Caspani, Ombretta 4 ; Chapman, Sonya C. 5 ; Di Stefano, Giulia 6 ; Finnerup, Nanna Brix 7 ; Garcia-Larrea, Luis 8 ; Goetz, Marcus 9 ; Kostenko, Anna 4 ; Pelz, Bernhard 10 ; Pogatzki-Zahn, Esther 11 ; Schubart, Karin 12 ; Stouffs, Alexandre 1 ; Truini, Andrea 6 ; Tracey, Irene 13 ; Troconiz, Iñaki F. 14 ; Van Niel, Johannes 15 ; Vela, Jose Miguel 16 ; Vincent, Katy 17 ; Vollert, Jan 18 ; Wanigasekera, Vishvarani 13 ; Wittayer, Matthias 4 ; Phillips, Keith G. 5 ; Treede, Rolf-Detlef 4 

 Institute of Neuroscience (IoNS), UCLouvain, Brussels, Belgium (GRID:grid.7942.8) (ISNI:0000 0001 2294 713X) 
 Translational Science & Intelligence, Grünenthal GmbH, Aachen, Germany (GRID:grid.428898.7) (ISNI:0000 0004 1765 3892) 
 Clinical Science Development, Grünenthal GmbH, Aachen, Germany (GRID:grid.428898.7) (ISNI:0000 0004 1765 3892) 
 University of Heidelberg, Department of Neurophysiology, Medical Faculty Mannheim, Mannheim, Germany (GRID:grid.7700.0) (ISNI:0000 0001 2190 4373) 
 Eli Lilly and Company, Erl Wood, UK (GRID:grid.418786.4) 
 Sapienza University, Department of Human Neuroscience, Rome, Italy (GRID:grid.7841.a) 
 Aarhus University, Danish Pain Research Center, Department of Clinical Medicine, Aarhus, Denmark (GRID:grid.7048.b) (ISNI:0000 0001 1956 2722) 
 Lyon Neurosciences Center Research Unit Inserm U 1028, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Lyon 1 University, Lyon, France (GRID:grid.413852.9) (ISNI:0000 0001 2163 3825) 
 MRC Systems GmbH, Heidelberg, Germany (GRID:grid.413852.9) 
10  MRC Systems GmbH, Heidelberg, Germany (GRID:grid.7700.0) 
11  University Hospital Münster, Department of Anaesthesiology, Intensive Care and Pain Medicine, Münster, Germany (GRID:grid.16149.3b) (ISNI:0000 0004 0551 4246) 
12  Consultech GmBH, Berlin, Germany (GRID:grid.16149.3b) 
13  University of Oxford, Wellcome Centre for Integrative Neuroimaging, Nuffield Department of Clinical Neurosciences, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
14  University of Navarra, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, Pamplona, Spain (GRID:grid.5924.a) (ISNI:0000000419370271) 
15  Mature Products Development, Grünenthal GmbH, Aachen, Germany (GRID:grid.428898.7) (ISNI:0000 0004 1765 3892) 
16  Drug Discovery & Preclinical Development, ESTEVE Pharmaceuticals, Barcelona, Spain (GRID:grid.428898.7) 
17  University of Oxford, Nuffield Department of Women’s and Reproductive Health (NDWRH), Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
18  Pain Research, Department of Surgery and Cancer, Imperial College London, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111) 
Pages
404
Publication year
2021
Publication date
Dec 2021
Publisher
BioMed Central
e-ISSN
17456215
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2730340652
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.