Demographic and Clinical Data

Between October 2011 and January 2013, 202 participants who had consulted their primary practitioner for symptoms of ADWA were included in the study. One patient, who signed the informed consent but did not fully perform the day 1 visit, was not randomized and was excluded from all analysis populations. Overall, 201 patients received at least one dose of the study treatments (safety set): 100 received etifoxine and 101 received alprazolam.

The baseline characteristics of the 201 patients from the safety set are presented in Table 1. At inclusion, the two groups were similar regarding nearly all the variables assessed, with a mean age of 39.4 years (range 18–64). The percentage of female patients was slightly higher in the etifoxine group: 76.0% vs. 70.3% in the alprazolam group. The mean weight of etifoxine patients was somewhat higher than alprazolam patients (80.7 and 76.4 kg, respectively), resulting in a higher body mass index in the etifoxine group (29.1 vs. 26.8 kg m−2).

Table 1 Patients baseline characteristics (safety set) Full size table

The main stressor responsible for the present episode of ADWA was related to family/love life (38.8% of patients), work/school (37.8%), finance (12.4%), or other issues (10.9%). The mean HAM-A total score at baseline was 29.9 (range 20–55), the mean (±standard deviation [SD]) CGI severity score was 3.8 (±1.0), with mean scores of 6 on the SDS subscales, reflecting the presence of illness that moderately disrupted the patients’ work, social life and family life. Mean (±SD) score on the MADRS was 12.4 (±4.6), indicative of low depressive symptoms.

Patient Disposition

Thirteen patients from the etifoxine group (13.0%) and 11 from the alprazolam group (10.9%) prematurely discontinued the study, mainly for adverse events (etifoxine: 4, alprazolam: 6) and consent withdrawal (etifoxine: 3, alprazolam: 2). Overall, 177 patients completed the study, 87 in the etifoxine group (87.0%) and 90 in the alprazolam group (89.1%). The mean (±SD) treatment duration was 26.6 ± 6.9 days in the etifoxine group (n = 99) and 27.3 ± 6.0 days in the alprazolam group (n = 99). Based on pill count, mean compliance rates with treatment were 97.2% in the etifoxine group (n = 98) and 98.5% in the alprazolam group (n = 98).

Efficacy Analysis

The FAS comprised 190 patients: 95 in etifoxine group and 95 in alprazolam group. Improvement of anxiety symptoms on day 28 was demonstrated in both groups, as reflected by a mean decrease in the HAM-A total score of 72.5% ± 23.8% and 79.7% ± 17.0% in the etifoxine and alprazolam groups, respectively (Fig. 1). The adjusted mean difference in HAM-A score of 1.78 [90% CI; 0.23, 3.33] was in favor of alprazolam, and as the upper limit of the 90% CI was greater than the 2.5 reference value, the non-inferiority of etifoxine compared with alprazolam was not shown (Table 2). On secondary outcome measures, there were no significant differences between the two groups at day 28 in the Self-Rated Assessment of ADWA symptoms, CGI scores, responder status, HAM-A psychic score, or SDS (Table 2) (Fig. 3).

Fig. 1 Progression of the mean (SD) HAM-A total score during the study (FAS). FAS Full analysis set, HAM-A Hamilton Anxiety Rating Scale, SD standard deviation Full size image

Table 2 Mean HAM-A scores adjusted for day 1 value (±SE) and percentage of responders during the study (FAS) Full size table

The benefits of treatment appeared from the first week with a mean decrease in the HAM-A score of 51.2% ± 22.5% and 58.7% ± 18.9% in the etifoxine and alprazolam groups, respectively, on day 7. There was an adjusted mean difference in HAM-A score of 2.19 [90% CI; 0.69, 3.70] and [95% CI; 0.40, 3.99] statistically significant in favor of alprazolam. However, 1 week after treatment discontinuation, HAM-A in the etifoxine group continued to decrease (−0.6 ± 4.5), while HAM-A in the alprazolam group increased (+2.2 ± 7.0) (p = 0.019) (Fig. 2). Thus, there was an adjusted mean difference in HAM-A score of −0.93 [90% CI; −2.96, 1.10] in favor of etifoxine, demonstrating non-inferiority of etifoxine compared with alprazolam at day 35 (Table 2). Similarly, on secondary outcome measures, there were no significant differences between groups at day 35 after treatment discontinuation, although scores numerically favored etifoxine at the later time point (Table 2) (Fig. 3). For example, CGI severity score decreased between day 28 and day 35 in the etifoxine group (−0.2 ± 0.8), while it increased in the alprazolam group (+0.2 ± 1.0), resulting in a significant difference between groups in the score change from day 28 to day 35 (p = 0.004).

Fig. 2 a Mean (SD) HAM-A total score and b CGI severity score at day 28 and day 35 (FAS). CGI Clinical Global Impression, FAS full analysis set; HAM-A Hamilton Anxiety Rating Scale, SD standard deviation Full size image

Fig. 3 a Progression of the mean HAM-A total score during the study, b progression of the HAM-A psychic sub-score and c progress of the HAM-A somatic sub-score adjusted for day 1 value (+SE) during the study (FAS). p values indicate significant scores. FAS full analysis set, HAM-A Hamilton Anxiety Rating Scale, SE standard error Full size image

Adverse Events

Adverse events were analyzed on the safety set (n = 201 patients). During the study, 35 patients (35.0%) in the etifoxine group experienced at least one adverse event compared to 48 (47.5%) in the alprazolam group (Table 3). During the treatment period (day 1–day 28), 35 patients (35.0%) experienced 70 adverse events in the etifoxine group compared to 44 patients (43.6%) who had 61 adverse events in the alprazolam group (p = 0.214). Adverse events were, however, markedly more often rated as “treatment-related” by the investigators in the alprazolam group (62.3%; 13 “possibly” and 25 “probably” related) than in the etifoxine group (34.3%; 13 “possibly” and 11 “probably” related) (p = 0.002).

Table 3 Safety results (safety set) Full size table

Adverse events resulted in treatment withdrawal in 7 patients from the etifoxine group and 6 patients from the alprazolam group, mainly due to central nervous system (CNS) and gastrointestinal symptoms. Indeed, CNS symptoms were the most frequent adverse events and were reported by 16.0% and 24.8% of the patients in the etifoxine and alprazolam group, respectively. Notably, many more patients reported episodes of “somnolence” or “sedation” in the alprazolam group (14 patients) than in the etifoxine group (4 patients). Additionally, “fatigue” events were only observed in patients who received alprazolam (4 patients). Gastrointestinal symptoms were also quite frequent and were reported by 12 patients in the etifoxine group and 8 in the alprazolam group. These various differences did not, however, reach statistical significance.

Four serious adverse events were reported by four patients (two in each group). In the etifoxine group, one patient underwent an arthroscopy consequent to a knee ligament injury and a second patient had a laparoscopic cholecystectomy to treat an episode of gallstone cholecystitis. Relationship with study treatment was judged by investigators “unrelated” and “unknown”, respectively. In the alprazolam group, one patient had suicidal ideation and was diagnosed with temporal lobe epilepsy, while a second one took an overdose of study treatment. Investigators considered the relationship with study treatment “unlikely” and “possible”, respectively for these events.

On day 35, the mean total DESS score was similar in the etifoxine and the alprazolam groups, with values of 2.0 (±4.4) and 3.0 (±5.4), respectively. After treatment discontinuation, notably more patients (11%) experienced adverse events in the alprazolam group (16 events) than in the etifoxine group (4% and 4 events) (p = 0.063). Among these adverse events, 50% were treatment-related in the alprazolam group (5 “possible” and 3 “probable”) compared to none in the etifoxine group.

Predictor Analyses

Univariate analyses indicated that women responded better to treatment (p = 0.045 at day 28, p = 0.017 at day 35), and that patients with high MADRS baseline scores responded worse to treatment (p = 0.025) at day 35. However, there was no significant link between response to treatment and the treatment administered (alprazolam or etifoxine), HAM-A baseline score, or other socio-demographic and clinical variables at these time points. Furthermore, on multivariate analysis, there were no significant predictors of treatment response.