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)

Trials

Irmgard Boesl¹  Karin Schubart²  Nanna Brix Finnerup³  Esther Pogatzki-Zahn⁴  Andrea Truini⁵  Giulia Di Stefano⁵  Matthias Wittayer⁶  Ombretta Caspani⁶  Anna Kostenko⁶  Rolf-Detlef Treede⁶  Iñaki F. Troconiz⁷  Jose Miguel Vela⁸  Sonya C. Chapman⁹  Keith G. Phillips⁹  André Mouraux^1,10  Alexandre Stouffs^1,10  Luis Garcia-Larrea^1,11  Marcus Goetz^1,12  Bernhard Pelz^1,12  Johannes Van Niel^1,13  Katy Vincent^1,14  Jan Vollert^1,15  Petra Bloms-Funke^1,16  Irene Tracey^1,17  Vishvarani Wanigasekera^1,17 

[1] Clinical Science Development, Grünenthal GmbH;Consultech GmBH;Danish Pain Research Center, Department of Clinical Medicine, Aarhus University;Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Münster;Department of Human Neuroscience, Sapienza University;Department of Neurophysiology, Medical Faculty Mannheim, University of Heidelberg;Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra;Drug Discovery & Preclinical Development, ESTEVE Pharmaceuticals;Eli Lilly and Company;Institute of Neuroscience (IoNS), UCLouvain;Lyon Neurosciences Center Research Unit Inserm U 1028, Pierre Wertheimer Hospital, Hospices Civils de Lyon, Lyon 1 University;MRC Systems GmbH;Mature Products Development, Grünenthal GmbH;Nuffield Department of Women’s and Reproductive Health (NDWRH), University of Oxford;Pain Research, Department of Surgery and Cancer, Imperial College London;Translational Science & Intelligence, Grünenthal GmbH;Wellcome Centre for Integrative Neuroimaging, Nuffield Department of Clinical Neurosciences, University of Oxford;

关键词: Pain;    Analgesics;    PK/PD;    EEG;    Biomarkers;    Laser-evoked potentials;   

DOI  :  10.1186/s13063-021-05272-y

来源: DOAJ

【 摘 要 】

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 ).

【 授权许可】

Unknown