Efficacy of THN102 (a combination of modafinil and flecainide) on vigilance and cognition during 40-hour total sleep deprivation in healthy subjects: Glial Connexins as a therapeutic target

AIMS: THN102 is a novel combination of modafinil and low-dose flecainide, targeting glial connexin activity to modulate modafinil effects. We investigated THN102 efficacy compared to modafinil and to placebo on vigilance and cognitive function during 40-h total sleep deprivation (TSD). METHODS: 20 healthy men participated in a double-blind, randomized, incomplete-block 3-period cross-over trial with 5 treatments (n=12 per group): placebo (PBO), modafinil 100 mg (MOD100), THN102 100/1, 100/3, 100/9 (modafinil 100mg and flecainide 1, 3 or 9 mg). Each period included a baseline day and a TSD day with treatments administered three times (01:00, 09:00 and 19:00). Reaction time in Psychomotor Vigilance Test (PVT), subjective somnolence and vital signs were assessed before and during treatment. Working memory (2-Back) and executive processes (Go/noGo for vigilance and inhibition, Wisconsin Card Sorting Task (WCST) for mental flexibility and Tower of London test for planning) were evaluated at 16:30. RESULTS: At 5-h post dose-1 (after 23-h TSD, primary endpoint), THN102 100/1 resulted in statistically higher PVT speed vs. MOD100 (3.97+/-0.09 vs. 3.74+/-0.14, p<0.05). No increase in effect was observed with higher flecainide doses in combinations. Most THN102 doses vs. MOD100 also improved the number of correct responses in 2-Back and Go errors in Go/noGo (p<0.05 for all doses), and perseverative responses in WCST (for 100/1 and 100/9). No impact on cardiac conduction was noted with THN102, and safety was similar to MOD100. CONCLUSIONS: THN102 seems more efficient than modafinil on vigilance, working memory and executive functions, opening new perspectives in management of hypersomnolence disorders.

2019
  • Sauvet F
  • Erblang M
  • Gomez-Merino D
  • Rabat A
  • Guillard M
  • Dubourdieu H
  • Lefloch H
  • Drogou C
  • Van Beers P
  • Bougard C
  • Bourrrilhon C
  • Arnal P
  • Rein W
  • Mouthon F
  • Brunner-Ferber F
  • Leger D
  • Dauvilliers Y
  • Chennaoui M
  • Charveriat M

CallNum: 

3.86
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  • Br J Clin Pharmacol
Aug 16;Epub ahead of print():