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A Single-Dose Etifoxine Neither Impairs Alertness Nor Cognitive Functions of the Elderly: a Randomized, Double-Blind, Placebo-Controlled Crossover Study D

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A Single-Dose Etifoxine Neither Impairs Alertness Nor Cognitive Functions of the Elderly: a Randomized, Double-Blind, Placebo-Controlled Crossover Study D P.1.g.031 A single-dose etifoxine neither impairs alertness nor cognitive functions of the elderly: a randomized, double-blind, placebo-controlled crossover study D. Deplanque 1,2 , F. Machuron 3, N. Waucquier 2, E. Jozefowicz 2, S. Duhem 2, S. Somers 2, O. Colin 1, A. Duhamel 3, R. Bordet 1 1Université Lille 2 - Faculté de Médecine, U1171 - Medical Pharmacology, Lille, France; 2CHU - Inserm, CIC 1403, Lille, France; 3CHU Lille, Biostatistics, Lille, France Introduction Study Registration: EudraCT 2012-005530-11 and NCT 02147548 Benzodiazepine prescription causes a number of problems, particularly due to its negative impact on alertness and memory, and more generally due to its effects on cognitive functions [1, 2]. Etifoxine hydrochloride (Stresam ®), a treatment indicated for psychosomatic manifestations of anxiety, could be an interesting alternative in elderly subjects, provided that this drug has been proven to have no negative impact on alertness, memory and, more broadly speaking, on cognitive functions in young subjects [3]. Objectives The primary objective of this study was to measure the impact of a single dose of etifoxine (100 mg), lorazepam (2 mg) or placebo on alertness in elderly subjects . The secondary objectives were to evaluate cognitive performances after administration of these treatments as well as to describe any adverse effects. Methods After Ethics committee approval, the Clinical Investigation Centre 1403 Inserm - Lille University Hospital (France) had recruited 30 healthy volunteers aged 65 to 75 who did not have any neurological or psychiatric history and had never used psychotropic drugs. According to a comparative, randomized placebo-controlled, double-blind crossover design, subjects underwent a total of 3 one-day sessions in a random order, each session separated by a wash-out period of at least 14 days. During each session, 2 hours after the treatment intake (either etifoxine, lorazepam or placebo), standardized cognitive tests were conducted using the Cambridge Neuropsychological Test Automated Batteries (CANTAB ®). A neuropsychologist also intervened for other cognitive evaluations including verbal memory (Rey Auditory Verbal Learning Test), verbal fluency, forward and backward digit span and Stroop tests. The primary endpoint was the reaction time (RTI), a parameter closely correlating with the alertness level. The primary endpoint was analyzed using a 3x3 latin square variance analysis. Results Table 1: Subjects’ characteristics at baseline The study population consisted of 30 healthy volunteers (10 males, 20 Baseline characteristics (N= 30) females, mean age 68 ± 3 years) (Table 1), recruited between December Men, n (%) 10 (33.3) 6th 2013 and October 7th 2015. All included subjects satisfied all inclusion Mean age (±SD), years 68.1 (± 2.9) criteria. Mean weight (±SD), kg 71.4 (± 14.5) Mean height (±SD), meters 1.67 (± 0.1) ® Primary endpoint: CANTAB Reaction Time Mean years of schooling (±SD) 12.1 (± 2.3) Compared to placebo, a single dose of 100 mg of etifoxine had no Occasional smokers, n (%) 1 (3.3) deleterious effect on alertness as evidenced by a non-significant Alcohol use, n (%) difference in reaction time to the CANTAB ® RTI test (RTI: 744.0 ± 146.8 Occasionally 17 (56.7) ms vs 770.3 ± 153.1 ms under placebo; p=0.789; Figure 1). Regularly ( ˂ ½ litre/ day) 6 (20) Current treatment* at screening, n (%) 26 (86.7) Figure 1: CANTAB ® Reaction Time *Aside from other psychoactive substances such as etifoxine or lorazepam. n (%): number and percentage of subjects; SD: Standard Deviation. Table 2: Etifoxine and lorazepam effects on attention, learning and memory performances Etifoxine Placebo N= Lorazepam Secondary endpoints Etifoxine 1 Lorazepam 1 N= 30 30 N= 30 Attention 486.8 RVP Mean latency (ms) 477.6(98.4) 562.7(130.6) p=1.0000 p ˂ 0.0001 (95.9) RVP A (p) Probability of 0.9(0.05) 0.9(0.05) 0.8(0.06) p=0.5624 p ˂ 0.0001 detecting the target sequence RVP Probability of correct responses (%) 0.5(0.2) 0.6(0.2) 0.4(0.2) p=0.3572 p ˂ 0.0001 Secondary endpoints RVP Total false alarm (n) 4.0 (3.2) 4.9 (5.6) 7.6 (7.5) p=1.0000 p=0.0272 Stroop Interference Time (s) 122.4 115.1(21.9) 138.9(40.0) Tests used to evaluate the attention showed that a single 100 mg p=0.4574 p=0.0004 dose of etifoxine has no deleterious effect. The CANTAB ® Rapid (33.7) Stroop Total errors (n) 2.9(3.5) 2.1 (2.4) 7.5(5.9) p = 0.6240 p ˂ 0.0001 Visual Information Processing (RVP) and the Stroop test gave Visuospatial memory comparable results with etifoxine and placebo. Compared to PAL Total errors 6 shapes 8.3 (8.9) 6.5 (5.9) 6.5 (6.6) p=1.0000 p = 1.0000 placebo, etifoxine caused no memory disorder, neither on adjusted (n) visuospatial, verbal nor on working memory. Lorazepam used as PAL First trial memory score (n) 9.6(3.8) 10(3.1) 9.9(3.9) p=0.9886 p=1.0000 2514.9 2606.9 3119.1 SRM Mean latency (ms) p = 1.0000 p = 0.0032 positive control, significantly impaired alertness, attention, working (653.1) (856.8) (1061.3) and verbal memories. Nevertheless, it did not alter visuospatial SRM Correct responses (%) 70.7(11.9) 72.7(12.2) 67.8(12.8) p=0.9056 p=0.1394 memory (Table 2). Verbal memory RAVLT Total correct answers 13.1 (1.8) 12 (2.6) 9.5 (4.1) p=0.1620 p=0.0008 Safety (n) A total of 87 adverse events (AEs) were reported under treatment. Working memory There were similar percentage of AEs observed with etifoxine SWM Between errors 4 to 10 50.9 (16.2) 53.9 (14.9) 61.9 (11.6) p=0.6634 p=0.0150 boxes (n) (n=12; 13.8%) and placebo (n=16; 18.4%), while AEs’ incidence SWM Strategy 6 to 10 boxes (n) 31.0 (5.1) 31.1 (4.6) 33.3 (4.3) p=1.0000 p=0.0064 was higher with lorazepam (n=59, 67.8%). Most AEs were DS Forward score (n) 9.2 (1.9) 9.4 (2.6) 8.7 (2.0) p=1.0000 p=0.0958 neurological, the most frequent being drowsiness that was rated as DS Backward score (n) 7.1 (1.9) 6.7 (2.1) 5.9 (2.2) p=0.4082 p=0.0188 severe once with etifoxine and four times with lorazepam. No Results are presented as mean (SD, standard deviation). RVP: Rapid Visual Information Processing, PAL: Paired Associates Learning; SRM: Spatial Recognition Memory; RAVLT: Rey Auditory Verbal Learning Test; SWM: serious adverse event occurred during the study. Spatial Working Memory; DS: Digit Span; %: percentage. 1 Bonferroni correction for multiple comparisons versus Conclusion placebo with p < 0.025. This study showed that a single 100 mg dose of etifoxine had no effect on alertness and did not impair cognitive functions in a population of healthy elderly as compared to placebo. In this way, etifoxine may be an interesting alternative to classic BZDs, considering its anxiolytic effects and the absence of possible adverse cognitive effects, especially in elderly subjects when an anxiolytic treatment is necessary. References Disclosure : Financial support of BIOCODEX [1] Billioti de Gage, S., Bégaud, B., Bazin, F., Verdoux, H., Dartigues, J.F., Pérès, K., Kurth, T., Pariente, A., 2012. Benzodiazepine use and risk of dementia: prospective population based study. Brit Med J 345, e6231. [2] Islam, M.M., Iqbal, U., Walther, B., Atique, S., Dubey, N.K., Nguyen, P.A., Poly, T.N., Masud, J.H., Li, Y.J., Shabbir, S.A., 2016. Benzodiazepine Use and Risk of Dementia in the Elderly Population: A Systematic Review and Meta-Analysis. Neuroepidemiology 47, 181-191. [3] Micallef, J., Soubrouillard, C., Guet, F., Le Guern, M.E., Alquier, C., Bruguerolle, B., Blin, O., 2001. A double blind parallel Group placebo controlled comparison of sedative and amnesic effects of etifoxine and lorazepam in healthy subjects. Fund Clin Pharmacol 15, 209-216.
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