Secukinumab in plaque psoriasis--results of two phase 3 trials.

BACKGROUND: Interleukin-17A is considered to be central to the pathogenesis of psoriasis. We evaluated secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe plaque psoriasis. METHODS: In two phase 3, double-blind, 52-week trials, ERASURE (Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis) and FIXTURE (Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis), we randomly assigned 738 patients (in the ERASURE study) and 1306 patients (in the FIXTURE study) to subcutaneous secukinumab at a dose of 300 mg or 150 mg (administered once weekly for 5 weeks, then every 4 weeks), placebo, or (in the FIXTURE study only) etanercept at a dose of 50 mg (administered twice weekly for 12 weeks, then once weekly). The objective of each study was to show the superiority of secukinumab over placebo at week 12 with respect to the proportion of patients who had a reduction of 75% or more from baseline in the psoriasis area-and-severity index score (PASI 75) and a score of 0 (clear) or 1 (almost clear) on a 5-point modified investigator's global assessment (coprimary end points). RESULTS: The proportion of patients who met the criterion for PASI 75 at week 12 was higher with each secukinumab dose than with placebo or etanercept: in the ERASURE study, the rates were 81.6% with 300 mg of secukinumab, 71.6% with 150 mg of secukinumab, and 4.5% with placebo; in the FIXTURE study, the rates were 77.1% with 300 mg of secukinumab, 67.0% with 150 mg of secukinumab, 44.0% with etanercept, and 4.9% with placebo (P<0.001 for each secukinumab dose vs. comparators). The proportion of patients with a response of 0 or 1 on the modified investigator's global assessment at week 12 was higher with each secukinumab dose than with placebo or etanercept: in the ERASURE study, the rates were 65.3% with 300 mg of secukinumab, 51.2% with 150 mg of secukinumab, and 2.4% with placebo; in the FIXTURE study, the rates were 62.5% with 300 mg of secukinumab, 51.1% with 150 mg of secukinumab, 27.2% with etanercept, and 2.8% with placebo (P<0.001 for each secukinumab dose vs. comparators). The rates of infection were higher with secukinumab than with placebo in both studies and were similar to those with etanercept. CONCLUSIONS: Secukinumab was effective for psoriasis in two randomized trials, validating interleukin-17A as a therapeutic target. (Funded by Novartis Pharmaceuticals; ERASURE and FIXTURE ClinicalTrials.gov numbers, NCT01365455 and NCT01358578, respectively.).

Clinical utility of the standardized observation tool Autism Behavior Coding System for early intervention research in autism spectrum disorder.

The Autism Behavior Coding System (ABCS) was developed to help evaluating the effectiveness of early intensive interventions in children with autism spectrum disorder (ASD). The video-based ABCS assesses eight core autistic behavioral variables during therapist-child interaction using standardized quantitative criteria, four behaviors according to their frequency of occurrence, four according to their duration. The present study focuses (1) on the correspondence of ABCS scores with scores on two standard clinical instruments (the ADOS-2 and an ASD-adaptation of the Children's Global Assessment Scale, DD-CGAS), (2) on the sensitivity to change of ABCS scores by the end of an intensive 18 days intervention period (EIP) and (c) on the predictability of short- and longer-term changes in social and repetitive behaviors from ABCS scores at baseline and EIP. Data from 51 children (42 M, 9 F; median age 45 months) followed over 1 year were available. There were significant correlations at baseline between several ABCS scores and ADOS-2 as well as DD-CGAS scores. Correlations at EIP between some ABCS and DD-CGAS scores were highly significant. Four ABCS scores reflected significant changes from baseline to EIP. Several baseline ABCS scores were predictive of DD-CGAS and ADOS-2 scores at EIP and Year 1. However, associations between ABCS score changes from baseline to EIP and the clinical scale changes by Year 1 were not significant. It is concluded that several ABCS scores have adequate clinical validity and sensitivity to change. The short-term changes in ABCS scores and their relationship to longer-term clinical changes need further study.

Short-Term and Highly Intensive Early Intervention FIAS: Two-Year Outcome Results and Factors of Influence.

BACKGROUND: Comprehensive behaviorally or developmentally based early intervention programs have been shown to be effective in improving cognitive, social communicative, and adaptive skills of children with autism spectrum disorder (ASD). Besides the definition of relevant outcome predictors, the question of whether early intensive intervention positively changes core autism symptoms in children, as well as their long-term outcome, is an important issue for current research. The primary objective of the current study was to examine whether symptomatic and behavioral changes in children up to 4.5 years with ASD were sustained one and two years after an initial 18 days of intensive FIAS (Frühintervention bei autistischen Störungen) intervention. METHODS: We analyzed the data of 32 young children with moderately severe to severe ASD who had been treated at the FIAS center between January 2011 and July 2017 and who had completed their 2-year follow-up in summer 2019. RESULTS: ADOS total scores decreased significantly from baseline to the 1-year follow-up and from baseline to the 2-year follow-up (p < 0.01), with the most prominent change being from baseline to 2-year follow-up. The DD-C-GAS, a global scale used to assess four areas of everyday functioning, showed highly significant improvements on all subdomains. We found mostly significant correlations between results on both rating instruments at all time points, yet mostly no meaningful correlation between their changes over time. There was a close and statistically significant relationship between parents' treatment adherence and ADOS scores, indicating that the better parents' treatment adherence, the lower the children scored on the ADOS at 1- and 2-year follow-up. Overall, improvement on both scales was virtually independent of age and autism symptom severity at baseline, suggesting that older (>43 months) and more severely affected children (ADOS total score >20) may benefit from the FIAS intervention to the same extent as younger children do. CONCLUSIONS: The results of the study indicate that the FIAS approach of providing an initial highly intensive 18-day intervention period, followed by 2 years of less intensive follow-up care had an impact on the core autism symptoms as well as the adaptive functioning of children with ASD.

Process research in early intensive intervention in autism spectrum disorder: Sensitivity to change of the autism behavior coding system.

The development of sensitive measures to capture changes in core autism symptoms is crucial in early intervention research. The study examines the sensitivity to change of the Autism Behavior Coding System (ABCS), a video-based instrument to assess core autism symptoms during therapist-child interaction. Video sequences of 40 young children treated in the Frühintervention bei Autistischen Störungen center were analyzed with regard to the question of whether short-term changes during an 18 day period of early intervention could be captured, and whether these results are reflected in an independent clinical assessment (Developmental Disorders-Child-Global Assessment Scale [DD-C-GAS]). ABCS results showed statistically significant improvements on behavioral domains such as "expression of wishes" and "social cooperative behavior" (P < 0.01), less pronounced on "eye contact." Improvements on the DD-C-GAS were highly significant on all subdomains. Both scales showed high correlations within their subdomains, yet no significant correlations between the changes in both instruments' scores were found. An additional analysis between the DD-C-GAS scores at day 18 and the changes in the ABCS scores showed statistically significant associations in the expected direction between the changes in the variable "eye contact" and all DD-C-GAS subdomains. The correspondence of the two levels of assessment is low, but the specifics of this relationship deserve further study. The ABCS may prove useful in addition to standard assessment tools, especially in early intervention research settings, as it allows reliable analysis of core behavioral elements in young children with autism. Autism Res 2019, 12: 1817-1828. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: The study examined the sensitivity of an autism-specific video coding system (ABCS) in assessing changes after an 18 day period of intensive early intervention. Video sequences of therapist-child-interaction of 40 young children with autism spectrum disorder (ASD) were analyzed. Children's behavior improved in expression of wishes, social cooperativity and eye contact. A therapist-based global assessment scale also showed important improvement after 18 days, yet both assessment instruments showed weak correlations between their respective changes. We showed that the ABCS may prove useful in capturing short-term changes in autism-related behaviors, especially in early intervention research.

Long-term retention on treatment with lumiracoxib 100 mg once or twice daily compared with celecoxib 200 mg once daily: a randomised controlled trial in patients with osteoarthritis.

BACKGROUND: The efficacy, safety and tolerability of lumiracoxib, a novel selective cyclooxygenase-2 (COX-2) inhibitor, has been demonstrated in previous studies of patients with osteoarthritis (OA). As it is important to establish the long-term safety and efficacy of treatments for a chronic disease such as OA, the present study compared the effects of lumiracoxib at doses of 100 mg once daily (o.d.) and 100 mg twice daily (b.i.d.) with those of celecoxib 200 mg o.d. on retention on treatment over 1 year. METHODS: In this 52-week, multicentre, randomised, double-blind, parallel-group study, male and female patients (aged at least 40 years) with symptomatic primary OA of the hip, knee, hand or spine were randomised (1:2:1) to lumiracoxib 100 mg o.d. (n = 755), lumiracoxib 100 mg b.i.d. (n = 1,519) or celecoxib 200 mg o.d. (n = 758). The primary objective of the study was to demonstrate non-inferiority of lumiracoxib at either dose compared with celecoxib 200 mg o.d. with respect to the 1-year retention on treatment rate. Secondary outcome variables included OA pain in the target joint, patient's and physician's global assessments of disease activity, Short Arthritis assessment Scale (SAS) total score, rescue medication use, and safety and tolerability. RESULTS: Retention rates at 1 year were similar for the lumiracoxib 100 mg o.d., lumiracoxib 100 mg b.i.d. and celecoxib 200 mg o.d. groups (46.9% vs 47.5% vs 45.3%, respectively). It was demonstrated that retention on treatment with lumiracoxib at either dose was non-inferior to celecoxib 200 mg o.d. Similarly, Kaplan-Meier curves for the probability of premature discontinuation from the study for any reason were similar across the treatment groups. All three treatments generally yielded comparable results for the secondary efficacy variables and all treatments were well tolerated. CONCLUSION: Long-term treatment with lumiracoxib 100 mg o.d., the recommended dose for OA, was as effective and well tolerated as celecoxib 200 mg o.d. in patients with OA. TRIAL REGISTRATION: clinicaltrials.gov NCT00145301.

Efficacy of ICS 205-930, a novel 5-hydroxytryptamine3 (5-HT3) receptor antagonist, in the prevention of migraine attacks. A complex answer to a simple question. ICS 205-930 Migraine Study Group.

To investigate whether the novel, potent and highly selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist ICS 205-930 can prevent migraine attacks, we conducted simultaneously two randomized, double-blind, placebo-controlled, multicentre, international trials, involving a total of 204 patients, suffering from classic or common migraine. Both trials had the same parallel-group design (1 month baseline observation, followed by 3 months treatment) and both produced remarkably similar results. The primary efficacy parameter was the proportional reduction in attack frequency recorded after 3 months of treatment. Twenty-two patients withdrew prematurely from the trials and could not be assessed for efficacy. Mild to severe constipation was reported by about 50% of the patients on active treatment. None of the doses of ICS 205-930 tested (50 mg, 25 mg and 15 mg daily) produced a statistically significantly better result to reduce attack frequency than did placebo. However, confidence intervals for the difference in effect with placebo were wide, indicating that 15 mg ICS 205-930 may produce a 57% reduction in attack frequency as compared to placebo. The most unusual finding was that, for all efficacy parameters, the best results were obtained with the lowest dose (15 mg), the worst results with the highest dose (50 mg) and an intermediate effect with 25 mg. Such an inverse relation between dose and efficacy suggests a bell-shaped dose-response curve, implying that doses lower than 15 mg might well prove to be more effective. Thus, the present study has produced inconclusive, but intriguing results. Lower doses should be further investigated before drawing any definite conclusion on the efficacy of ICS 205-930 in the prophylactic treatment of migraine.