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European journal of pain
By Besson M, Matthey A, Daali Y and 4 others.
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N-desmethyl clobazam (NDMC), an α2-preferring-α1-sparing-GABAA modulator, was promising in preclinical models and Phase I studies, demonstrating antihyperalgesic properties without associated sedation. This Phase IIa trial aimed at exploring the effect of NDMC in peripheral neuropathic pain (NP) patients.
Randomised, ascending doses, double-blind, placebo-controlled study, evaluating 40, 60, 120 mg of NDMC. Primary outcome was the change in weekly average daily pain (WADP) on a Numerical Rating Scale (NRS) from baseline (V1) to the end of the study (V7). Secondary outcomes included sedation (subjective NRS), quality of life (SF36), global and patient impression of change (CGI, PCGI). PK and safety data were collected. The study was prematurely terminated due to recruitment challenges related to the COVID-19 pandemic.
Thirty-three out of the planned 76 patients were enrolled. The mean reduction in WADP from V1 to V7 was -1.53 points for placebo and -1.99 across all NDMC doses (delta = 0.46, p = 0.47). When analysed according to NDMC plasma concentrations, the mean WADP reduction was 1.53 (SD 1.58) for placebo 1.78 (SD 1.79) for NDMC < 1000 ng/mL, and 2.40 (SD 1.46) for NDMC ≥ 1000 ng/mL. The prevalence of 30% pain reduction was 38.5% (placebo) and 83.3% (NDMC ≥ 1000 ng/mL). Logistic regression analysis indicated that NDMC ≥ 1000 ng/nL was predictive of a 30% pain reduction (odds ratio = 12.5, p = 0.04). NDMC was well tolerated.
Despite being underpowered, this study revealed a consistent exposure-response relationship along with a favourable safety profile for NDMC in patients with NP.
ClinicalTrial.gov (NCT03375034); kofam.ch (SNCTP000003517). Significance statement: This work presenting the Phase II data of the new antihyperalgesic compound, N-Desmethyl-Clobazam (NDMC) in peripheral neuropathic pain patients support further investigation into the role in modulating GABAergic pathways as a potential therapeutic target for neuropathic pain. This objective is particularly relevant given the limited efficacy of standard pharmacological treatments for neuropathic pain, which often requires a multimodal approach targeting the multiple pathways involved in pain pathophysiology.
Published in European journal of pain (London, England). The abstract is shown as published and remains the work of its authors; read the full article at the source.
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