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)

Abstract

Background Few new drugs have been developed for chronic pain. Drug development is challenged by uncertainty about whether the drug engages the human target sufficiently to have a meaningful pharmacodynamic effect. IMI2-PainCare-BioPain-RCT1 is one of four similarly designed studies that aim to link different functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics. This study focusses on biomarkers derived from nerve excitability testing (NET) using threshold tracking of the peripheral nervous system. Methods This is a multisite single-dose, subject and assessor-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD), and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from NET of large sensory and motor fibers and small sensory fibers using perception threshold tracking 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 with at least 1 week apart. Motor and sensory NET will be assessed on the right wrist in a non-sensitized normal condition while perception threshold tracking will be performed bilaterally on both non-sensitized and sensitized forearm skin. Cutaneous high-frequency electrical stimulation is used to induce hyperalgesia. Blood samples will be taken for pharmacokinetic purposes and pain ratings as well as predictive psychological traits will be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split across the two primary outcomes: strength-duration time constant (SDTC; a measure of passive membrane properties and nodal persistent Na+ conductance) of large sensory fibers and SDTC of large motor fibers comparing lacosamide and placebo. The key secondary endpoint is the SDTC measured in small sensory fibers. Remaining treatment arm effects on key NET outcomes and PK modelling are other prespecified secondary or exploratory analyses. Discussion Measurements of NET using threshold tracking protocols are sensitive to membrane potential at the site of stimulation. Sets of useful indices of axonal excitability collectively may provide insights into the mechanisms responsible for membrane polarization, ion channel function, and activity of ionic pumps during the process of impulse conduction. IMI2-PainCare-BioPain-RCT1 hypothesizes that NET can serve as biomarkers of target engagement of analgesic drugs in this compartment of the nociceptive system 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 (2019-000942-36).

The test–retest reliability of large and small fiber nerve excitability testing with threshold tracking

“…This study was designed on the basis of IMI2-PainCare-BioPain-RCT1, which is a multicenter clinical trial ( Nochi et al, 2022 ). In addition to large fiber NET variables as primary endpoints, the small fiber PTT is a secondary endpoint measure in the IMI2-PainCare-BioPain-RCT1 trial.…”

Pharmacological Probes to Validate Biomarkers for Analgesic Drug Development

“…Its goal is fulfilment of the objectives of Call H2020-JTI-IMI2-10B of the IMI. Details of the studies conducted in healthy subjects to identify and validate pharmacodynamic biomarkers of nociceptive processing in humans are published elsewhere [ 6 , 7 , 8 , 9 , 10 , 11 ].…”

“…In June 2018, Medline and clinicaltrials.gov were searched to identify candidate drugs with analgesic properties for consideration by IMI-PainCare; subsequently, four clinical trials were planned and registered with EudraCT [ 6 , 7 , 8 , 9 ], the designs of three of which have been published [ 10 , 11 , 12 ]. “Analgesics” [MeSH Major Topic] was the primary search term in Medline; this was further refined with “pain” [MeSH Major Topic], “systematic review” [Publication Type] and “humans” [MeSH Terms], eventually resulting in the inspection of 761 publications (see Figure 2 for a flow diagram).…”

“…Whereas some biomarkers are selective readouts for a given compartment of the nociceptive system (e.g., small-fibre perception threshold tracking as a readout of nociceptive processing at the level of the peripheral nervous system), other biomarkers are dependent on the state of nociceptive processing along the entire neuraxis (e.g., laser-evoked brain potentials that are sequentially processed and transmitted at peripheral, spinal cord and brain levels). These biomarkers will be tested across four parallel clinical studies (RCT1 [ 6 , 11 ], RCT2 [ 7 , 12 ], RCT3 [ 8 , 10 ] and RCT4 [ 9 ]) using three pharmacological probes (lacosamide, pregabalin and tapentadol) that are expected to predominantly affect nociceptive processing at peripheral, spinal and brain levels, respectively. Nonetheless, all three probes are active in multiple compartments.…”

“…In this publication, we describe our methodology to identify drugs that could be used as pharmacological probes for the validation of pharmacodynamic biomarkers of nociceptive processing in humans and discuss the advantages and limitations of the identified probes. Based on these considerations, four randomized clinical studies have been initiated for the validation of biomarkers [ 6 , 7 , 8 , 9 , 10 , 11 ] ( Figure 1 ).…”