Objective: To determine whether etifoxine, a non-benzodiazepine drug of the benzoxazine family, is non-inferior compared with clonazepam in the treatment of anxiety disorders.
Method: A randomized controlled double blind trial with parallel groups was conducted. A total of 179 volunteer patients with a diagnosis of anxiety disorder (DSM-IV), between 18 and 64 years of age, participated in this study. The experimental group received 150 mg/day of etifoxine and the control 1 mg/day of clonazepam, both in three daily doses for 12 weeks. This treatment was completed by 87 participants, and 70 were available for follow-up at 24 weeks from start of treatment. The primary objective was a non-inferiority comparison between etifoxine and clonazepam in the decrease of anxiety symptoms (HAM-A) at 12 weeks of treatment. Secondary outcomes included the evaluation of medication side effects (UKU), anxiety symptoms at 24 weeks of treatment, and clinical improvement (CGI). Data analysis included multiple imputation of missing data. The effect of etifoxine on the HAM-A, UKU, and CGI was evaluated with the intention of treatment, and a sensitivity analysis of the results was conducted. Non-inferiority would be declared by a standardized mean difference (SMD) between clonazepam and etifoxine not superior to 0.31 in favour of clonazepam.
Results: Using imputed data, etifoxine shows non-inferiority to clonazepam on the reduction of anxiety symptoms at the 12-week (SMD = 0.407; 95% CI, 0.069, 0.746) and 24-week follow-ups (SMD = 0.484; 95% CI, 0.163, 0.806) and presented fewer side effects (SMD = 0.58; 95% CI, 0.287, 0.889). LOCF analysis shows that etifoxine is non-inferior to clonazepam on reduction of anxiety symptoms and adverse symptoms even when no change was assigned as result to participant whom withdrew. Non-inferiority could be declared for clinical improvement (SMD = 0.326; 95% CI, - 0.20, 0.858).
Conclusion: Etifoxine was non-inferior to clonazepam on reduction of anxiety symptoms, adverse effects, and clinical improvement.
Keywords: Anxiety; Benzodiazepines; Clonazepam; Etifoxine; Non-inferiority trial.