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)

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).

IMI2-PainCare-BioPain-RCT1: study protocol for 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 peripheral nerve excitability testing (NET)

“…The IMI-PainCare ( http://imi-paincare.eu ) is a research consortium with participants from 14 countries including academic institutions, European Federation of Pharmaceutical Industries and Associations (EFPIA), Small and medium-sized enterprises (SMEs), patient organizations and pain societies. The overall concept of the BioPain subtopic of IMI-PainCare has been described previously [ 2 ]. In short, we hypothesize that different biomarkers of the peripheral, spinal cord, and brain compartments of the nociceptive system can be used to assess drug exposure and target engagement to be used in the development of new analgesics and possibly also in clinical trials in pain patients.…”

“…BioPain includes four similarly designed randomized controlled trials (RCT) using different biomarkers of peripheral nerve excitability (IMI2-PainCare-BioPain-RCT1) 1 , spinal cord and brainstem reflex activity (IMI2-PainCare-BioPain-RCT2) 2 , electroencephalographic measures of brain activity (IMI2-PainCare-BioPain-RCT3) 3 [ 2 ], and functional magnetic resonance imaging measures of brain activity (IMI2-PainCare-BioPain-RCT4) 4 .…”

“…The objective of the overall BioPain has been presented previously [ 2 ]. IMI2-PainCare-BioPain-RCT1 will thus focus on biomarkers derived from peripheral nerve excitability testing (NET) [ 3 – 6 ].…”

“…After completion of Patient-Reported Outcomes Measures (PROMS), HFS will be applied to the left forearm. Pharmacodynamic (PD) testing consisting of NET will be evaluated before and three times after a single dose of lacosamide, pregabalin, tapentadol, and placebo, given in four separate study periods separated by at least 1 week, as described previously for IMI2-PainCare-BioPain-RCT3 [ 2 ] (Fig. 1 ).…”

“…Subjects are asked to rate the intensity of pain and unpleasantness after each PD (NET) sessions. PROMS will be collected additionally two times to assess subjective pain perception, and validated questionnaires will be used to assess psychological traits and states [ 2 ]. Five blood samples will be taken to measure plasma drug levels for pharmacokinetics.…”