Etifoxine is non-inferior than clonazepam for reduction of anxiety symptoms in the treatment of anxiety disorders: a randomized, double blind, non-inferiority trial.

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.

Design and statistical considerations for studies evaluating the efficacy of a single dose of the human papillomavirus (HPV) vaccine.

Cervical cancer is a leading cause of cancer mortality in women worldwide. Human papillomavirus (HPV) types 16 and 18 cause about 70% of all cervical cancers. Clinical trials have demonstrated that three doses of either commercially available HPV vaccine, Cervarix ® or Gardasil ®, prevent most new HPV 16/18 infections and associated precancerous lesions. Based on evidence of immunological non-inferiority, 2-dose regimens have been licensed for adolescents in the United States, European Union, and elsewhere. However, if a single dose were effective, vaccine costs would be reduced substantially and the logistics of vaccination would be greatly simplified, enabling vaccination programs in developing countries. The National Cancer Institute (NCI) and the Agencia Costarricense de Investigaciones Biomédicas (ACIB) are conducting, with support from the Bill & Melinda Gates Foundation and the International Agency for Research on Cancer (IARC), a large 24,000 girl study to evaluate the efficacy of a 1-dose regimen. The first component of the study is a four-year non-inferiority trial comparing 1- to 2-dose regimens of the two licensed vaccines. The second component is an observational study that estimates the vaccine efficacy (VE) of each regimen by comparing the HPV infection rates in the trial arms to those in a contemporaneous survey group of unvaccinated girls. In this paper, we describe the design and statistical analysis for this study. We explain the advantage of defining non-inferiority on the absolute risk scale when the expected event rate is near 0 and, given this definition, suggest an approach to account for missing clinic visits. We then describe the problem of estimating VE in the absence of a randomized placebo arm and offer our solution.

Overcoming barriers to HPV vaccination: non-inferiority of antibody response to human papillomavirus 16/18 vaccine in adolescents vaccinated with a two-dose vs. a three-dose schedule at 21 months.

For middle and low-income countries, the cost of HPV vaccines remains challenging. We conducted an open-label nonrandomized clinical trial evaluating immune response to the HPV-16/18 AS04-adjuvanted vaccine administered on a standard (months (M) 0-1-6) versus extended schedule (M 0-6-60) at 7, 21, 60, 72 and 120 months post-vaccination. Participants were females recruited in Morelos, Mexico: 474 girls aged 9-10 years and 500 women aged 18-24 years receiving a standard schedule, and 1026 girls aged 9-10 years receiving an extended schedule (currently the girls in the extended schedule had received only the first 2 doses). This report presents the interim analysis results for non-inferiority between the regimes conducted with the current available data at 21 months after the first dose, with serum antibodies assessed by ELISA. A pre-stated margin of non-inferiority was defined by post-vaccination geometric mean titer (GMT) ratio (upper 95% confidence interval [CI]≤2.0) between the standard and the two-dose schedule in girls at month 21. Immune response to the vaccine was strongest in adolescent girls and in the 3-dose group. Statistical non-inferiority of the two-dose versus three-dose groups was demonstrated. At 21 months, comparing the adolescent 2-dose versus 3-dose groups, the GMT ratio and 95% CI were 1.66 (1.55-1.81) and 1.67 (1.51-1.86) for HPV16 and 18, respectively. The two-dose regimen was non-inferior when compared to the three-dose response in same-age girls and with women aged 18-24 years after 21 months of follow-up. The reduction in the number of doses from the current three-dose schedule may lower overall costs associated with the vaccination and increase accessibility and compliance with the recommended dosing of the HPV vaccine.