IMI2-PainCare-BioPain-RCT2 protocol: a randomized, double-blind, placebo-controlled, crossover, multicenter trial in healthy subjects to investigate the effects of lacosamide, pregabalin, and tapentadol on biomarkers of pain processing observed by non-invasive neurophysiological measurements of human spinal cord and brainstem activity.
Background: IMI2-PainCare-BioPain-RCT2 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on specific compartments of the nociceptive system that could serve to accelerate the future development of analgesics. IMI2-PainCare-BioPain-R...
| Publicado en: | Trials Vol. 23; no. 1; pp. 1 - 27 |
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| Autores principales: | , , , , , , , , , , , , , , , , , , , |
| Formato: | protocol tables/charts Journal Article |
| Publicado: |
BioMed Central
9/5/2022
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=158904770&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 158904770 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 17456215 38OC jtl: Trials issn: 17456215 maglogo: N pubinfo: dt: 9/5/2022 vid: 23 iid: 1 pid: 24147 pub: BioMed Central artinfo: ui: 158904770 158904770 NLM36064434 158904770 10.1186/s13063-022-06431-5 NLM36064434 158904770 ppf: 1 ppct: 26 formats: tig: atl: IMI2-PainCare-BioPain-RCT2 protocol: a randomized, double-blind, placebo-controlled, crossover, multicenter trial in healthy subjects to investigate the effects of lacosamide, pregabalin, and tapentadol on biomarkers of pain processing observed by non-invasive neurophysiological measurements of human spinal cord and brainstem activity. aug: au: Leone, Caterina Di Stefano, Giulia Di Pietro, Giuseppe Bloms-Funke, Petra Boesl, Irmgard Caspani, Ombretta Chapman, Sonya C. Finnerup, Nanna Brix Garcia-Larrea, Luis Li, Tom Goetz, Marcus Mouraux, André Pelz, Bernhard Pogatzki-Zahn, Esther Schilder, Andreas Schnetter, Erik Schubart, Karin Tracey, Irene Troconiz, Inaki F. Van Niel, Hans affil: Department of Human Neuroscience, Sapienza University, Rome, Italy sug: subj: Spinal Cord Pain Analgesics Adverse Effects Research Subjects Brain Stem Multicenter Studies Funding Source ab: Background: IMI2-PainCare-BioPain-RCT2 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on specific compartments of the nociceptive system that could serve to accelerate the future development of analgesics. IMI2-PainCare-BioPain-RCT2 will focus on human spinal cord and brainstem activity using biomarkers derived from non-invasive neurophysiological measurements.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. Neurophysiological biomarkers of spinal and brainstem activity (the RIII flexion reflex, the N13 component of somatosensory evoked potentials (SEP) and the R2 component of the blink reflex) will be recorded before and at three distinct time points 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 on neurophysiological measures will be assessed in a clinically relevant hyperalgesic condition (high-frequency electrical stimulation of the skin), and in a non-sensitized normal condition. Patient-reported outcome measures (pain ratings and predictive psychological traits) will also be collected; and blood samples will be taken for pharmacokinetic modelling. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split between the two primary endpoints, namely the percentage amplitude changes of the RIII area and N13 amplitude under tapentadol. Remaining treatment arm effects on RIII, N13 and R2 recovery cycle are key secondary confirmatory analyses. Complex statistical analyses and PK-PD modelling are exploratory.Discussion: The RIII component of the flexion reflex is a pure nociceptive spinal reflex widely used for investigating pain processing at the spinal level. It is sensitive to different experimental pain models and to the antinociceptive activity of drugs. The N13 is mediated by large myelinated non-nociceptive fibers and reflects segmental postsynaptic response of wide dynamic range dorsal horn neurons at the level of cervical spinal cord, and it could be therefore sensitive to the action of drugs specifically targeting the dorsal horn. The R2 reflex is mediated by large myelinated non-nociceptive fibers, its circuit consists of a polysynaptic chain lying in the reticular formation of the pons and medulla. The recovery cycle of R2 is widely used for assessing brainstem excitability. For these reasons, IMI2-PainCare-BioPain-RCT2 hypothesizes that spinal and brainstem neurophysiological 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 on 02 February 2019 in EudraCT ( 2019-000755-14 ). pubtype: Academic Journal doctype: protocol tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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