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)

Alexandre Stouffs,Andrea Truini,Johannes Niel ,Petra Bloms‐Funke ,Karin Schubart,Luis Garcia-Larrea,Iñaki F. Trocóniz ,Irmgard Boesl,Marcus Goetz,Esther Pogatzki-Zahn ,Giulia Di Stefano,Nanna Brix Finnerup ,Sonya C. Chapman,Ombretta Caspani,Irene Tracey,Anna Kostenko,André Mouraux ,Matthias Wittayer,Rolf‐Detlef Treede ,Keith G. Phillips ,Jan Vollert,José Miguel Vela ,Bernhard Pelz,Katy Vincent,Vishvarani Wanigasekera

doi:10.1186/s13063-021-05272-y

Abstract

BackgroundIMI2-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.MethodsThis 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.DiscussionLEPs 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 registrationThis trial was registered 25/06/2019 in EudraCT (2019%2D%2D001204-37).

Highlights

Background and rationale {6a} Currently available pharmacological therapies provide inadequate relief for many patients with chronic pain
Early deselection of unpromising candidates would greatly reduce attrition rates in clinical development. This was encouraged by the recently revised European Medicines Agency (EMA)/CHMP Guideline on the clinical development of medicinal products intended for the treatment of pain (EMA/ CHMP/970057/2011). We postulate that this could be achieved by using a novel research paradigm taking advantage of improved objective measures of nociceptive signal processing, functional biomarkers of pain which translate between animals and humans, and pharmacokinetic-pharmacodynamic (PK-PD) modeling
By identifying specific mechanisms within pain pathways in healthy volunteers, these same quantitative neurophysiological biomarkers have the opportunity—if well validated in patients—to permit patient stratification and enrichment in later clinical trials as encouraged by the EMA/CHMP/970057/2011 Guideline. This could accelerate the development of novel analgesics in several ways: preclinical prediction could be improved by using translatable readouts across species; clinical Phase 1 trials could benefit from biomarkers of target engagement and from human surrogate models predictive of clinical efficacy; clinical Phase 2 and 3 studies could benefit from tools for patient stratification

Summary

Introduction

Background and rationale {6a} Currently available pharmacological therapies provide inadequate relief for many patients with chronic pain. By identifying specific mechanisms within pain pathways in healthy volunteers, these same quantitative neurophysiological biomarkers have the opportunity—if well validated in patients—to permit patient stratification and enrichment in later clinical trials as encouraged by the EMA/CHMP/970057/2011 Guideline. This could accelerate the development of novel analgesics in several ways: preclinical prediction could be improved by using translatable readouts across species; clinical Phase 1 trials could benefit from biomarkers of target engagement and from human surrogate models predictive of clinical efficacy; clinical Phase 2 and 3 studies could benefit from tools for patient stratification. IMI2-PainCare-BioPain-RCT3 will focus on biomarkers derived from non-invasive electroencephalographic (EEG) measures of brain activity.

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