RESUMEN
Studies conducted to support registration or approval of veterinary anthelmintics generally follow study design recommendations provided by the VICH (International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products), "Efficacy of Anthelmintics: General Requirements" (VICH GL7). For dose confirmation studies, VICH GL7 provides recommendations for determining that the control animals had an adequate infection "to permit the appropriate standards of efficacy to be met with acceptable statistical and biological certitude/confidence." In the simulation studies described in this report, we investigated the performance of one method, the statistical criterion given in Section 4.5 of VICH GL7, for evaluating the adequacy of infection in anthelmintic studies, in combination with the conventional criterion of a minimum of six adequately infected animals. We conducted numerical simulations, based on parasite data from previously conducted dose confirmation studies in dogs and cattle, to investigate how the statistical criterion impacts adequacy of infection determinations when used with the conventional criterion at various sample sizes. Simulation studies in common nematode species in both dogs and cattle indicated that under certain circumstances the statistical criterion can guard against overinterpreting the evaluation of adequacy of infection as sample size is increased. However, the statistical criterion may be overly restrictive for samples with adequate infection but containing multiple zero parasite counts and adding it to the conventional criterion does not provide any additional benefit when the sample contains no zero counts. It is important for investigators designing efficacy studies to understand the potential impact this criterion may have when establishing adequacy of infection criteria in study protocols.
Asunto(s)
Ensayos Clínicos como Asunto/normas , Helmintos/efectos de los fármacos , Neuropéptidos/farmacología , Animales , Interpretación Estadística de Datos , Helmintiasis Animal/tratamiento farmacológico , Cooperación Internacional , Medicina Veterinaria/normasRESUMEN
OBJECTIVE: To determine the association of plasma B lymphocyte stimulator (BLyS) levels, immunosuppressive therapy, and other clinical parameters with disease activity in systemic lupus erythematosus (SLE). METHODS: Two hundred forty-five SLE patients were evaluated prospectively over a 2-year period at 4 centers. Assessments were performed every 3-6 months. Univariate analysis was used to determine the association among the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, serum anti-double-stranded DNA (anti-dsDNA), and plasma BLyS levels. A multivariate repeated-measures model incorporating immunosuppressive therapy was utilized. RESULTS: Ninety-two percent of the patients were female. Sixty-seven percent were white, 31% African American, and 2% Asian (all of these groups may include Hispanic). Mean values at baseline were as follows: age 41.5 years, disease duration 8.1 years, SELENA-SLEDAI 3.3 (median 2, range 0-18), BLyS 5.57 ng/ml, IgG 1,439 mg/dl, C3 104.4 mg/dl, and C4 21.3 mg/dl; among those positive for anti-dsDNA, the median titer was 1:40 (range 1:10-1:1,280). Univariate analysis showed that plasma BLyS levels were associated with anti-dsDNA titers (P = 0.0465) and SELENA-SLEDAI scores (P = 0.0002). In multivariate analyses, a greater increase in the SELENA-SLEDAI score from the previous visit was associated with higher BLyS levels at the previous visit (P = 0.0042) and with a greater increase in the BLyS level from the previous visit (P = 0.0007). CONCLUSION: The findings of association between a greater increase in the BLyS level from the previous visit and a greater increase in the SELENA-SLEDAI score at the subsequent visit, and between an elevated BLyS level at the previous visit and a greater SELENA-SLEDAI score at the subsequent visit, demonstrate a relationship between circulating BLyS levels and SLE disease activity. These results lend support to the notion that BLyS is a candidate for therapeutic targeting in SLE.