a randomized double blind placebo controlled phase 1 study of multiple ascending doses of subcutaneous m1095 an anti interleukin 17a f nanobody in moderate to severe psoriasis

Background Interleukin 17 is involved in the pathogenesis of psoriasis, a chronic debilitating disease. Objectives To evaluate the safety/tolerability, immunogenicity, pharmacokinetics/pharmacodynamics, and efficacy of M1095, an anti–interleukin 17A/F nanobody, in moderate-to-severe plaque psoriasis. Methods This multicenter, double-blind, placebo-controlled dose escalation phase 1 study randomized 44 patients 4:1 to treatment with subcutaneous M1095 (30, 60, 120, or 240 mg) or placebo biweekly for 6 weeks, in 4 ascending dose cohorts. Results The most frequent treatment-emergent adverse events with M1095 were pruritus (n = 4) and headache (n = 3); 2 patients withdrew owing to adverse events (injection site reaction and elevated liver enzyme levels). The terminal half-life of M1095 was 11 to 12 days. The area under the curve/maximum concentration was dose proportional. Of 10 M1095-treated patients positive for antidrug antibodies, 5 showed treatment-emergent antidrug antibody responses. There was no effect on M1095 exposure. Marked decreases in psoriasis inflammatory markers were observed with M1095. By day 85, 100% and 56% of patients receiving M1095, 240 mg, achieved psoriasis area and severity index 90 and 100, respectively. Improvements in static Physician's Global Assessment and affected body surface area were also seen. Limitations Interpretation of efficacy data is limited by the small sample size. Conclusion Multiple subcutaneous doses of M1095 showed a favorable safety profile with dose-dependent improvements in psoriasis

The incidence of arthropathy adverse events in efalizumab-treated patients is low and similar to placebo and does not increase with long-term treatment: pooled analysis of data from Phase III clinical trials of efalizumab

A large-scale, pooled analysis of safety data from five Phase III clinical trials (including open-label extensions of two of these studies) and two Phase III open-label clinical trials of efalizumab was conducted to explore whether arthropathy adverse events (AEs) were associated with efalizumab treatment in patients with moderate-to-severe chronic plaque psoriasis. Data from patients who received subcutaneous injections of efalizumab or placebo were stratified for analysis into phases according to the nature and duration of treatment. These included: the ‘first treatment’ phase (0–12-week data from patients who received either efalizumab, 1 mg/kg once weekly, or placebo in the five placebo-controlled studies); the ‘extended treatment’ phase (13–24-week data from seven trials for all efalizumab-treated patients); and the ‘long-term treatment’ phase (data from efalizumab-treated patients who received treatment for up to 36 months in two long-term trials). Descriptive statistics were performed and the incidence of arthropathy AEs per patient-year was calculated using 95% confidence intervals (CIs). During the first treatment phase, a similar proportion of patients had an arthropathy AE in the efalizumab group (3.3%; 58/1740 patients) compared with the placebo group (3.5%; 34/979 patients); the incidence of arthropathy AEs per patient-year was 0.15 in the efalizumab group (95% CI 0.11–0.19) and 0.16 in the placebo group (95% CI 0.11–0.22). Analysis of first treatment phase data from one study (n = 793) showed that the incidence of psoriatic arthropathy per patient-year was lower in efalizumab-treated patients (0.10; 95% CI 0.05–0.18) than in those given placebo (0.17; 95% CI 0.08–0.30). During the extended treatment phase, the incidence of arthropathy remained low (0.17; 95% CI 0.14–0.22). Data from two long-term studies showed that there was no increase in the incidence of arthropathy AEs over time in patients treated with efalizumab for up to 36 months. Patients who had an arthropathy AE during treatment with efalizumab appeared to be more likely to have a history of arthropathy prior to treatment. Efalizumab does not appear to increase the risk of arthropathy AEs compared with placebo

Du bon usage des tests dans les essais cliniques

Les inférences multiples sont présentes dans de nombreux essais cliniques et soulèvent des problèmes d’analyse et d’interprétation si elles ne sont pas correctement prises en compte. L’écueil à éviter est de considérer à tort l’existence d’une différence statistiquement significative. Pour ce faire, on a recours à des méthodes statistiques adéquates. Leur utilisation n’est toutefois pas systématique et dépend fortement des objectifs de l’essai.Multiplicity of inferences is present in a large majority of clinical trials and conducts to false analyses or interpretation issues. The main risk consists in false positive conclusions. A large number of statistical methods is available for controlling the rate of false positive conclusions. But formal adjustment is not necessary in all cases and depends on the aims of the study

Du bon usage des tests dans les essays cliniques

Les inférences multiples sont présentes dans de nombreux essais cliniques et soulèvent des problèmes d’analyse et d’interprétation si elles ne sont pas correctement prises en compte. L’écueil à éviter est de considérer à tort l’existence d’une différence statistiquement significative. Pour ce faire, on a recours à des méthodes statistiques adéquates. Leur utilisation n’est toutefois pas systématique et dépend fortement des objectifs de l’essai

Patient subgroup analyses of the treatment effect of subcutaneous interferon β-1a on development of multiple sclerosis in the randomized controlled REFLEX study

The REFLEX study (NCT00404352) established that subcutaneous (sc) interferon (IFN) beta-1a reduced the risks of McDonald MS (2005 criteria) and clinically definite multiple sclerosis (CDMS) in patients with a first clinical demyelinating event suggestive of MS. The aim of this subgroup analysis was to assess the treatment effect of sc IFN beta-1a in patient subgroups defined by baseline disease and demographic characteristics (age, sex, use of steroids at the first event, classification of first event as mono- or multifocal, presence/absence of gadolinium-enhancing lesions, count of < 9 or a parts per thousand yen9 T2 lesions), and by diagnosis of MS using the revised McDonald 2010 MS criteria. Patients were randomized to the serum-free formulation of IFN beta-1a, 44 mu g sc three times weekly or once weekly, or placebo, for 24 months or until diagnosis of CDMS. Treatment effects of sc IFN beta-1a on McDonald 2005 MS and CDMS in the predefined subgroups were similar to effects found in the intent-to-treat population. McDonald 2010 MS was retrospectively diagnosed in 37.7 % of patients at baseline. Both regimens of sc IFN beta-1a significantly reduced the risk versus placebo of McDonald 2005 MS and CDMS, irrespective of McDonald 2010 status at baseline (risk reductions between 29 and 51 %). The effect of sc IFN beta-1a was not substantially influenced by baseline patient demographic and disease characteristics, or baseline presence/absence of McDonald 2010 MS