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In health technology assessment (HTA), beside network meta-analysis (NMA), indirect comparisons (IC) have become an important tool used to provide evidence between two treatments when no head-to-head data are available. Researchers may use the adjusted indirect comparison based on the Bucher method (AIC) or the matching-adjusted indirect comparison (MAIC). While the Bucher method may provide biased results when included trials differ in baseline characteristics that influence the treatment outcome (treatment effect modifier), this issue may be addressed by applying the MAIC method if individual patient data (IPD) for at least one part of the AIC is available. Here, IPD is reweighted to match baseline characteristics and/or treatment effect modifiers of published data. However, the MAIC method does not provide a solution for situations when several common comparators are available. In these situations, assuming that the indirect comparison via the different common comparators is homogeneous, we propose merging these results by using meta-analysis methodology to provide a single, potentially more precise, treatment effect estimate. This paper introduces the method to combine several MAIC networks using classic meta-analysis techniques, it discusses the advantages and limitations of this approach, as well as demonstrates a practical application to combine several (M)AIC networks using data from Phase III psoriasis randomized control trials (RCT).

Summary Background Interleukin‐17 antagonists have received a first‐line label for moderate‐to‐severe plaque psoriasis. Objectives We conducted the first head‐to‐head trial between the two most commonly used first‐line therapies in Germany, fumaric acid esters (FAEs) and methotrexate, and the interleukin‐17A antagonist, ixekizumab. Methods Systemic‐naive patients were randomized in this parallel‐group, active‐comparator, open‐label, rater‐blinded trial (each group n = 54). The primary outcome was the proportion of patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at 24 weeks. Key secondary outcomes included 24‐week PASI 90 and 100, static Physician's Global Assessment (sPGA) score of 0 or 1, and Dermatology Life Quality Index (DLQI) score of 0 or 1. Safety events at week 24 were analysed using Fisher's exact test. Missing data were imputed using nonresponder imputation. The trial was registered at ClinicalTrials.gov (NCT02634801) and EudraCT (2015‐002649‐69). Results At week 24, more ixekizumab‐treated patients achieved PASI 75 [91% vs. 22% FAEs (P < 0·001) and 70% methotrexate (P = 0·014)], PASI 90 [80% vs. 9% FAEs (P < 0·001) and 39% methotrexate (P < 0·001)] and PASI 100 [41% vs. 4% FAEs (P < 0·001) and 13% methotrexate (P = 0·0041)], as well as sPGA (0,1) and DLQI (0,1). Conclusions Ixekizumab was superior in inducing PASI 75/90/100, sPGA (0,1) and DLQI (0,1) responses at week 24 compared with methotrexate and FAEs. Safety profiles for all treatments were consistent with prior studies., What's already known about this topic? Fumaric acid esters (FAEs) and methotrexate are two frequently used conventional systemic therapies for chronic plaque psoriasis.A recent meta‐analysis of methotrexate showed a ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75) rate of 45·2% from primary end points at either 12 or 16 weeks.Until recently, FAEs were licensed for psoriasis only in Germany, but were used in many other European countries as off‐label treatment of psoriasis. In 2017, the European Medicines Agency approved dimethyl fumarate, presumed to be the main active ingredient of FAEs, for the treatment of adult patients with moderate‐to‐severe chronic plaque psoriasis. What does this study add? This study is the first randomized, head‐to‐head trial comparing a biologic treatment with these therapies in a systemic‐treatment‐naive patient population.This study shows the low tolerability of FAEs leading to a significant discontinuation rate, the better tolerability and moderate efficacy of methotrexate, and the good tolerability, fast onset of action and high efficacy of ixekizumab in an unbiased comparison.Our findings reinforce the favourable risk–benefit profile of ixekizumab shown previously and provide further evidence of its efficacy at 24 weeks. https://doi.org/10.1111/bjd.18905 available online

Proceedings of the 53rd Hawaii International Conference on System Sciences | 2020 The article of record as published may be found at https://doi.org/10.24251/HICSS.2020.773 The fifth generation (5G) technological leap has arrived, bringing with it promises of incredible data rates and never before seen precision in location accuracy. However this self-same precision carries with it the significant question: how will it be protected? These questions form the underlying motivation for this article where we examine 5G architecture which employs a radio access part commonly termed a cloud or centralized radio access network (C-RAN). The C-RAN centralizes higher-level physical layer processes while keeping lowlevel processes distributed throughout the physical network. We show how this architecture both increases location-based privacy through improved physical-layer security, but creates new privacy concerns via the extension of the radio access network through fronthauls connecting data transfer among low and high-level processing. Concurrently, the proposed 5G variable subcarrier spacing further exacerbates the former point. Through simulation we quantify the decrease in location privacy given the aforementioned considerations. It is shown that location privacy is inversely proportional to subcarrier spacing for user equipment (UE) connected to multiple 5G access points. Specifically, for a (UE) using the widest allowable subcarrier spacing location privacy drops to approximately three meters.

BACKGROUND: Head-to-head randomised studies comparing ixekizumab and secukinumab in the treatment of psoriasis are not available.OBJECTIVE: Assess efficacy and quality of life with ixekizumab vs. secukinumab treatment using matching-adjusted indirect comparisons.METHODS: Psoriasis Area and Severity Index (PASI) improvement of at least 75%, 90% and 100% and Dermatology Life Quality Index (DLQI) 0/1 response rates for approved doses of ixekizumab (160 mg at Week 0, then 80 mg every two weeks for the first 12 weeks) and secukinumab (300 mg at Weeks 0, 1, 2, 3 and 4, then 300 mg every 4 weeks) treatment were compared using data from active (etanercept and ustekinumab) and placebo-controlled studies. Comparisons were made using the Bucher (BU) and two modified versions of the Signorovitch method (SG total and SG separate). Subsequently, results based on active treatment common comparators were combined using generic inverse-variance meta-analysis.RESULTS: In meta-analysis of studies with active comparators, PASI 90 response rates were 12.7% (95% CI: 5.5%-19.8%; p=0.0005), 10.0% (2.1%-18.0%; p=0.01) and 11.2% (3.2%-19.1%; p=0.006) higher and PASI 100 response rates 11.7% (5.9%-17.5%; pCONCLUSION: Ixekizumab had higher PASI 90 and PASI 100 responses at Week 12 compared to secukinumab using adjusted indirect comparisons. This article is protected by copyright. All rights reserved.

Background Biologics are effective for the treatment of psoriasis. However, treatment outcomes may differ among biologic-naive patients and those switched from previous biological therapies. Objectives The study's objective was to investigate efficacy and safety of ixekizumab, a high-affinity anti-interleukin-17A antibody, in patients with psoriasis with and without previous exposure to biologics. Methods Data were integrated from the 12-week induction phase of two etanercept-controlled Phase III trials. Patients received 80 mg ixekizumab every 2 weeks (IXE Q2W; N = 736) or every 4 weeks (IXE Q4W; N = 733) following a 160-mg starting dose, or placebo (N = 361). Etanercept (50 mg twice weekly; N = 740) was administered as active control. Psoriasis Area and Severity Index (PASI) 75, PASI 90 and PASI 100 response rates at week 12 were evaluated in patients with or without previous exposure to biologics. Treatment effects were analysed with the Cochran–Mantel–Haenszel test stratified by study; missing values were imputed as non-response. Results Overall, 497 (19.3%) patients had prior exposure to biologics and 2073 (80.7%) were naive to biologic therapy. PASI 75 was achieved by 91.5% of biologic-experienced patients and 87.7% of biologic-naive patients for IXE Q2W, 76.2% and 82.2% for IXE Q4W, respectively, and 34.6% and 50.7%, respectively, for etanercept. Higher response rates favouring each ixekizumab dose over etanercept within subgroups were also seen regarding PASI 90 and PASI 100. Conclusions Contrary to etanercept, the efficacy of ixekizumab was similarly high in patients with and without previous exposure to biologics when administered 80 mg every 2 weeks.

Introduction The conduct of structured benefit-risk assessment (BRA) of pharmaceutical products is a key area of interest for regulatory agencies and the pharmaceutical industry. However, the acceptance of a standardized approach and implementation are slow. Statisticians play major roles in these organizations, and have a great opportunity to be involved and drive the shaping of future BRA. Method We performed a literature search of recent reviews and initiatives assessing BRA methodologies, and grouped them to assist those new to BRA in learning, understanding, and choosing methodologies. We summarized the key points and discussed the impact of this emerging field on various stakeholders, particularly statisticians in the pharmaceutical industry. Results We provide introductory, essential, special interest, and further information and initiatives materials that direct readers to the most relevant materials, which were published between 2000 and 2013. Based on recommendations in these materials we supply a toolkit of advocated BRA methodologies. Discussion Despite initiatives promoting these methodologies, there are still barriers, one of which being the lack of a consensus on the most appropriate methodologies among stakeholders. However, this opens up opportunities, for statisticians in the pharmaceutical industry especially, to champion appropriate BRA methodology use throughout the pharmaceutical product lifecycle. Conclusions This article may serve as a starting point for discussions and to reach a mutual consensus for methodology selection in a particular situation. Regulators and pharmaceutical industry should continue to collaborate to develop and take forward BRA methodologies, and by clear communication develop a mutual understanding of the key issues. Copyright © 2015 John Wiley & Sons, Ltd.

Evidence of the cost-efficacy of ixekizumab for the treatment of moderate-to-severe plaque psoriasis (PsO) in the US is limited.To estimate the number needed to treat (NNT) and monthly cost of achieving one additional Psoriasis Area and Severity Index (PASI) 75, 90, and 100 responder for ixekizumab and other Food and Drug Administration (FDA)-approved biologics in PsO.A network meta-analysis estimated the probability of achieving PASI 75, 90, or 100 response during induction for each biologic. NNTs were calculated using response difference of each respective biologic vs placebo at the end of induction. Monthly costs per additional PASI responder were based on FDA-approved doses, wholesale acquisition costs, and induction NNTs.Induction NNTs for ixekizumab 80 mg once every 2 weeks (Q2W) relative to placebo were consistently lower across all levels of clearance compared with the other biologics. Monthly cost per additional responder was lowest for ustekinumab 45 mg at PASI 75 and for secukinumab 300 mg and ixekizumab 80 mg Q2W at PASI 90. Ixekizumab 80 mg Q2W had the lowest cost for PASI 100.In this analysis, ixekizumab is the most cost-efficient biologic in the US when targeting complete resolution, as measured by PASI 100 in PsO.

This study aimed to compare the effectiveness of duloxetine (DLX) and the anticonvulsants pregabalin (PGB) and gabapentin (GBP) for the treatment of diabetic peripheral neuropathic pain (DPNP) in routine clinical care.Data from a 6-month, noninterventional study involving 2575 patients in whom treatment of DPNP was initiated with or changed to DLX, PGB, or GBP (n=1523) were analyzed post hoc; patients treated with other medications or combinations were excluded from this analysis. Propensity scoring was used to compare patient groups, assessing Brief Pain Inventory (BPI), Clinical and Patient Global Impression (CGI/PGI), the Hospital Anxiety and Depression Scale (HADS), the Sheehan Disability Scale (SDS), and the Short Form Health Survey (SF 12).Mean median daily dosage over 6 months was 53.9 mg for DLX (N=931), 173.5 mg for PGB (N=248), and 727.8 mg for GBP (N=351). BPI average pain severity (last observation carried forward, mean [SD]) decreased by 2.3 [2.30] points for DLX patients, and by 1.9 [2.22] in PGB, and 1.1 [2.15] in GBP patients. This difference remained statistically significant (DLX vs. PGB: P=0.029; DLX vs. GBP: P0.001) after adjustment by propensity scores. Similar findings were also seen for the BPI interference score, CGI and PGI, the HADS anxiety score, the HADS depression score.When compared with DLX, the low doses of PGB and GBP used in this noninterventional study might have contributed to the lower effectiveness found for both anticonvulsants in the treatment of patients with DPNP.

Objective Pain control is the main objective when treating patients with painful diabetic peripheral neuropathic pain (DPNP). However, DPNP is associated with further substantial patient burden that often is not appropriately addressed. Our study identified patients' needs and asked patients what they expected from DPNP treatment. Methods Baseline data were collected in a German prospective, non-interventional study in patients with DPNP starting or switching pain medication at the discretion of the investigator. DPNP severity was evaluated using Brief Pain Inventory (BPI) and Clinician/Patient Global Impression-Severity (CGI-S/PGI-S). Primary objective of this study was to evaluate for which interference item of the BPI DPNP patients expected most to improve due to DPNP therapy. Results We enrolled 2,576 patients with DPNP from 307 outpatient centers (mean [standard deviation {SD}] age: 65.8 years [11.5], 51.2% female). Mean (SD) CGI-S and PGI-S at baseline were 4.4 (0.91) and 4.5 (1.05), respectively. BPI average pain score was 5.1 (2.04). The BPI interference score was 4.8 (2.18); items most impaired at baseline were walking ability 5.5 (2.60) and general activity 5.4 (2.37). The most frequently chosen BPI interference items expected to improve as a result of the pain treatment were: General activity (29.3%; 95% confidence interval [CI] 27.5–31.0%) and walking ability (24.4%; 95% CI 22.8–26.1%), followed by sleep (14.7%), enjoyment of life (13.6%), mood (8.3%), normal work (7.7%), and relations with other people (1.9%). Conclusions The majority of patients identified “general activity” and “walking ability” as most relevant BPI interference items for which they expect improvement from DPNP treatment.

Objectives To contrast the analgesic effect of duloxetine with antidepressants reported in other published randomized clinical trials (RCTs) and review articles in patients with chronic low back pain (CLBP). Methods In this narrative review, the results of 13 RCTs and 5 systematic reviews examining the analgesic effect of various antidepressants in CLBP were contrasted with those of 3 placebo-controlled duloxetine RCTs. Treatment effects based on the Brief Pain Inventory (BPI) average score in the duloxetine RCTs were assessed in all completers (by study and overall) and in last-observation-carried-forward (LOCF) analyses (extracted from study reports). 30%- and 50%-reduction response rates were compared between duloxetine and placebo. Results Eleven different antidepressants were examined in 13 individual RCTs. Sample sizes, treatment durations, and analysis methods varied across studies. Reviews each included 5 to 9 of the RCTs and came to different conclusions regarding the analgesic effect of antidepressants: 2 found no evidence while 3 reported some evidence. The completer analysis showed greater improvements in BPI average scores with duloxetine vs. placebo (significant in 2 studies). Overall, the least square mean (standard error) difference between treatments was − 0.7 (0.15) (P

In this study we analyze the impact of organization leaders on their fellows’ behavior in academia by utilizing the unique structure of the Max Planck Society. The latter is a leading research organization in Europe with autonomous institutes which center around appointed directors. Using panel data of commercialization activities and royalties received in the period 1980–2007, we observe that both director engagement in disclosure activity and royalty shares received at the institute level lead to a significant increase in invention disclosure by non-directors in the following year. Yet, both effects are only significant when regarding short-term time lags of one year. Utilizing information based on a survey performed with Max Planck scientists in 2007 we find that scientists’ perceived academic relevance of commercialization neither relates to previous director involvement in disclosure activity nor to previous overall disclosure efforts within the institute. We conclude that directors have a short-term...

Using a new dataset with detailed geographic information about licensing activities of the German Max Planck Society, we analyze how the probability and magnitude of commercial success are affected by geographic distance between licensors and licensees. Our evidence suggests that proximity does not generally lead to superior commercialization outcomes. A significantly negative association between distance and commercialization success is identified only for foreign licensees within the subsample of inventions licensed to more than one firm. Positive associations between distance and performance indicators are not robust to controlling for invention quality or selection into licensing.

Assessment of severity is essential for the management of chronic diseases. Continuous variables like scores obtained from the Hamilton Rating Scale for Depression or the Psoriasis Area and Severity Index (PASI) are standard measures used in clinical trials of depression and psoriasis. In clinical trials of psoriasis, for example, the reduction of PASI from baseline in response to therapy, in particular the proportion of patients achieving at least 75%, 90%, or 100% improvement of disease (PASI 75, PASI 90, or PASI 100), is typically used to evaluate treatment efficacy. However, evaluation of the proportions of patients reaching absolute PASI values (eg, ≤1, ≤2, ≤3, or ≤5) has recently gained greater clinical interest and is increasingly being reported. When relative versus absolute scores are standard, as is the case with the PASI in psoriasis, it is difficult to compare absolute changes using existing published data. Thus, we developed a method to estimate absolute PASI levels from aggregated relative levels. This conversion method is based on a latent 2-dimensional normal distribution for the absolute score at baseline and at a specific endpoint with a truncation to allow for baseline inclusion criterion. The model was fitted to aggregated results from simulations and from 3 phase III studies that had known absolute PASI proportions. The predictions represented the actual results quite precisely. This model might be applied to other conditions, such as depression, to estimate proportions of patients achieving an absolute low level of disease activity, given absolute values at baseline and proportions of patients achieving relative improvements at a subsequent time point.

This study questions whether a lower starting dose of duloxetine (DLX) could be beneficial for patients with depression, in terms of tolerability and safety in routine clinical care.Post-hoc analyses of a multicenter, prospective, non-interventional, 6-month study in adult outpatients with a depressive episode was undertaken.Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), discontinuations due to TEAEs and hospitalizations due to depression, were all documented at 2 weeks, 4 weeks, 3 months and 6 months after treatment initiation/switch to DLX.Of 4517 patients enrolled, 4313 were included for TEAE evaluation. TEAEs occurred in 17.2% of patients, and SAEs occurred in 0.79% of patients, including one case of suicidal ideation. 1404 patients discontinued within 6 months (TEAEs: n = 119). Starting treatment with 30 mg/day DLX (72.7%) was favored in females, or after inadequate efficacy of previous antidepressant treatment; 60 mg/day DLX was favored in more severe depression and patients receiving concomitant pain medication.Initiating treatment with 60 mg/day DLX was not associated with poorer tolerability in this study. Physicians may be guided by their clinical experience to carefully consider the individual benefit/risk ratio and TEAE susceptibility when deciding to start treatment with a higher or a lower dose of DLX.

The second generation antipsychotics clozapine and olanzapine are known to cause weight gain. However, only clozapine is associated with drug-induced fever. Cytokines have been linked to the induction of both weight gain and drug-induced fever. We investigated these potential side effects of clozapine and olanzapine and studied their differential effects on cytokine secretion. Thirty patients suffering from schizophrenia, schizophreniform disorder or schizoaffective disorder were treated with either clozapine (mean modal dose: 266.7+/-77.9mg) or olanzapine (21.2+/-2.5mg) in a randomized, double-blind, 6-week study. Body mass index (BMI), tympanic temperature, and plasma levels of leptin and cytokines (tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptor 1 and 2 (sTNFR-1/2), soluble interleukin-2 receptors (sIL-2R), interleukin-6) were determined weekly. BMI, leptin and cytokines significantly increased over time, except interleukin-6 and sTNFR-1 in the olanzapine group. All cytokines numerically increased compared to baseline already during the first week of treatment in both groups. Leptin, TNF-alpha, sTNFR-1, sTNFR-2 and sIL-2R levels correlated with the BMI. Five patients who received clozapine (33%) developed drug-induced fever (>/=38 degrees C). In these, interleukin-6 peak levels were significantly (p

The second generation antipsychotics clozapine and olanzapine frequently induce weight gain. Randomized studies investigating abnormal eating behavior (food craving, binge eating) possibly associated with weight gain are lacking. Thirty patients with schizophrenia, schizophreniform, or schizoaffective disorder were included in this randomized, double-blind, parallel study comparing abnormal eating behavior using a standardized scale, clinical efficacy using the Brief Psychiatric Rating Scale 0-6 and Clinical Global Impression-Severity scale, and tolerability of clozapine and olanzapine. In both treatment groups, the number of patients reporting food craving, binge eating, or both increased over time. The likelihood to experience food craving at any time during drug treatment showed a trend (P = 0.068) to be higher in the olanzapine group (48.9%) compared with the clozapine group (23.3%). The likelihood to experience binge eating at any time during drug treatment was numerically but not statistically significantly higher in the olanzapine group (16.7%) than in the clozapine group (8.9%). In both groups, significant baseline-to-end point improvements of clinical symptoms (Brief Psychiatric Rating Scale 0-6: clozapine, 36.6 +/- 8.8 to 15.9 +/- 13.7; olanzapine, 36.7 +/- 9.9 to 19.1 +/- 13.8) and severity of illness (Clinical Global Impression-Severity scale: clozapine, 4.7 +/- 0.6 to 2.5 +/- 1.5; olanzapine, 4.5 +/- 0.6 to 2.3 +/- 1.2) were observed. These improvements did not differ significantly between groups. Olanzapine was more tolerable than clozapine; adverse events occurred significantly (P < 0.01) less frequently than in the clozapine group. These results suggest that both clozapine and olanzapine can induce food craving and binge eating, however, olanzapine possibly to a greater extent. Findings on clinical efficacy and safety are in accordance with previous reports.

Objective: This post hoc analysis aimed to determine whether patients with major depressive disorder (MDD) in duloxetine trials who were antidepressant naive or who were previously exposed to antidepressants exhibited differences in efficacy and functioning. Method: Data were pooled from 15 double-blind, placebo- and/or active-controlled duloxetine trials of adult patients with MDD conducted by Eli Lilly and Company. The individual studies took place between March 2000 and November 2009. Data were analyzed using 4 pretreatment subgroups: first-episode never treated, multiple-episode never treated, treated previously only with selective serotonin reuptake inhibitors (SSRIs), and previously treated with antidepressants other than just SSRIs. Measures included the 17-item Hamilton Depression Rating Scale (HDRS-17) total and somatic symptom subscale scores, Montgomery-Asberg Depression Rating Scale (MADRS) total score, and Sheehan Disability Scale total score. Response rates (50% and 30%) were based on the HDRS-17 total score and remission rates on either the HDRS-17 or MADRS total score. Results: Response and remission rates were significantly greater (P < .05 in 11 of 12 comparisons) for duloxetine versus placebo in the 4 subgroups. A trend of greater response and remission occurred for first-episode versus multiple-episode patients; both groups were generally higher than the antidepressant-treated groups. Mean changes in efficacy measures were mostly significantly greater (P < .05 in 13 of 16 comparisons) for duloxetine versus placebo within each pretreatment subgroup, with some (P < .05 in 2 of 24 comparisons) significant interaction effects between subgroups on HDRS-17 total and somatic symptoms scores. Conclusions: Duloxetine was generally superior to placebo on response and remission rates and in mean change on efficacy measures. Response and remission rates were numerically greater for first-episode versus multiple-episode and drug-treated patients. Mean change differences on efficacy measures among the 4 subgroups were inconsistent. Duloxetine showed a similar therapeutic effect independent of episode frequency and antidepressant pretreatment.

We evaluated individual patient data from phase II to IV clinical trials of duloxetine in major depressive disorder (MDD) (34 studies, 13,887 patients). Our goal was to identify clusters of patients with similar depressive symptom patterns at baseline, as measured by the 17-item Hamilton Depression Rating Scale (HAMD-17), and to investigate their respective predictive value of outcomes as measured by the HAMD-17 total score. Five clusters were identified at baseline: 1) "Lack of insight"; 2) "Sleep/sexual/somatic"; 3) "Typical MDD"; 4) "Gastrointestinal/weight loss"; and 5) "Mild MDD". However, it should be noted that cluster descriptors are not mutually exclusive. Analyses of the HAMD-17 total score results over time were performed using the 18 randomized placebo and/or actively controlled studies representing 6723 patients. At the end of acute treatment (ranging from 4 to 36 weeks), different levels of effect sizes for active therapy (64.5% duloxetine) vs. placebo were detected by cluster. In 3 out of 5 clusters (representing about 80% of the patients), the effect size was significantly different from 0, in favor of active therapy. The effect size was largest in those clusters with severe somatic symptoms ("Sleep/sexual/somatic" cluster [-0.4170], and "Gastrointestinal/weight loss" cluster [-0.338]). In conclusion, our cluster analysis identified 5 clinically relevant MDD patient clusters with specific mean treatment outcomes. Identification of MDD clusters may help to improve outcomes by adapting MDD treatment to particular clinical profiles.

This multicentre, double-blind, parallel-group study in diabetic peripheral neuropathic pain addressed whether, in patients not responding to standard doses of duloxetine or pregabalin, combining both medications is superior to increasing each drug to its maximum recommended dose. For initial 8-week therapy, either 60 mg/day duloxetine (groups 1, 2) or 300 mg/day pregabalin (groups 3, 4) was given. Thereafter, in the 8-week combination/high-dose therapy period, only nonresponders received 120 mg/day duloxetine (group 1), a combination of 60 mg/day duloxetine and 300 mg/day pregabalin (groups 2, 3), or 600 mg/day pregabalin (group 4). Primary outcome (Brief Pain Inventory Modified Short Form [BPI-MSF] 24-hour average pain change after combination/high-dose therapy) was analyzed comparing combination (groups 2, 3 pooled) with high-dose monotherapy (groups 1, 4 pooled). Secondary end points included response rates, BPI-MSF severity items, and comparison of duloxetine and pregabalin in BPI-MSF average pain. Eight hundred four patients were evaluated for initial therapy and 339 for combination/high-dose therapy. There were no significant differences between combination and high-dose monotherapy regarding BPI-MSF average pain (mean change: combination: -2.35; high-dose monotherapy: -2.16; P = 0.370) and most secondary end points, which, however, consistently favoured combination therapy. Fifty-percent response rates were 52.1% for combination and 39.3% for high-dose monotherapy (P = 0.068). In exploratory analyses of the initial 8-week therapy uncorrected for multiple comparisons, 60 mg/day duloxetine was found superior to 300 mg/day pregabalin (P < 0.001). Both drugs and their combination were well tolerated. Although not significantly superior to high-dose monotherapy, combination therapy was considered to be effective, safe, and well tolerated.

Mental illness has been observed to follow a neuroprogressive course, commencing with prodrome, then onset, recurrence and finally chronic illness. In bipolar disorder and schizophrenia responsiveness to treatment mirrors these stages of illness progression, with greater response to treatment in the earlier stages of illness and greater treatment resistance in chronic late stage illness. Using data from 5627 participants in 15 controlled trials of duloxetine, comparator arm (paroxetine, venlafaxine, escitalopram) or placebo for the treatment of an acute depressive episode, the relationship between treatment response and number of previous depressive episodes was determined. Data was dichotomised for comparisons between participants who had >3 previous episodes (n=1697) or ≤3 previous episodes (n=3930), and additionally for no previous episodes (n=1381) or at least one previous episode (n=4246). Analyses were conducted by study arm for each clinical trial, and results were then pooled. There was no significant difference between treatment response and number of previous depressive episodes. This unexpected finding suggests that treatments to reduce symptoms of depression during acute illness do not lose efficacy for patients with a longer history of illness.

Several post-hoc studies have shown that lack of early improvement reduces the chance of later response or remission. This post-hoc analysis evaluates different cut-off points of non-improvement at 4 weeks of escitalopram treatment to predict 8-week non-response and non-remission.This study consisted of MDD patients with an absence of improvement (30% reduction in baseline score of the HAMD-17) at Week 4 of escitalopram treatment (10mg/day) that continued escitalopram treatment (10-20mg/day) for a further 4-week period (n=251). Predictive, sensitivity and specificity values for the several definitions of non-improvement (≤ 25%, ≤ 20% and ≤ 15% reduction in the HAMD-17 baseline total score) at 4 weeks were calculated.Overall, 70.1% (176/251) of patients did not achieve response at Week 8 and 84.5% (212/251) did not achieve remission. The predictive value for non-response was high (71.4-74.3%) for all cut-off points of non-improvement tested. The respective values for non-remission were placed between 85.0% and 87.2%.This was a post-hoc subgroup analysis. The only drug assessed was escitalopram.Our data indicate that an absence of improvement,30% reduction in the HAMD-17, after 4 weeks of escitalopram treatment should prompt clinicians to consider a change in treatment strategy. Similar findings were previously reported for other antidepressants.

Data on inability to work from an observational study in patients treated with duloxetine for major depressive disorder in clinical practice in Germany were collected. Ability to work was compared between baseline and up to 6 months after initiation of duloxetine. All patients with a working status at baseline other than retired or retired early were included. 2,825 patients were analyzed, 54.8% were able to work at baseline increasing to 83.8% at 6 months. Of those patients unable to work at baseline, 72.7% were able to work after 6 months. A relevant reduction of inability to work was also found for patient subgroups with moderate to severe pain at baseline and those with and without MDD pretreatment. As inability to work is one of the main cost drivers for depressive patients in Germany, the reduction of inability to work could potentially result in considerable cost savings for health insurance companies and society.

Demographic transition and the decreasing number of medical experts in rural areas create a growing demand for tele-medicine systems that allow remote patient monitoring. Especially in the context of heart diseases, the possibility to transmit electrocardiograph (ECG) data in a streaming mode is of high interest. However, available cellular networks with protocols like GPRS, EDGE or UMTS are highly unreliable due to frequent connection interruptions and high bandwidth variations for data traffic. In this paper, we present a system suitable for live ECG-streaming over UMTS. We describe a usability experiment of the system within the context of the Berlin-Marathon, a huge event with 40.000 participants - 5 of them carrying devices with our software for live ECG streaming. The systems successfully demonstrated the use of near-field Bluetooth communication between electronic health care devices and a home broker in conjunction with mobile communication via UMTS. The forthcoming Fontane system builds upon experiences collected with the current prototype. We present these experiences and discusses some of the challenges of live streaming of medical data across unreliable heterogeneous networks.

To evaluate the effect of atomoxetine on quality of life (QoL) and family burden in children and adolescents with attention deficit/hyperactivity disorder (ADHD) and comorbid oppositional defiant (ODD) or conduct disorder (CD).This secondary analysis was based on a randomized, double-blind, 9-week study of atomoxetine (target dose 1.2 mg/kg body weight) versus placebo. The study included 180 patients (atomoxetine 121, placebo 59), aged 6-17 years. QoL was measured using the KINDL-R questionnaire. The total score encompasses six dimensions (or subscales) measuring QoL in terms of "physical well-being", "emotional well-being", "self-esteem", "friends", "family", and "school". Family burden of illness was measured using the FaBel questionnaire.With atomoxetine, the KINDL-R total score improved significantly (P = 0.021) more than with placebo. This improvement also applied to the subscales except for "physical well-being" (opposite effect) and "school" (no effect). No significant treatment group differences were seen on the FaBel questionnaire. No differences were found between the fast and slow titration groups in terms of ADHD, ODD, and disruptive behavior severity. Furthermore, no such differences were observed for QoL and family burden.This study suggests positive effects of atomoxetine on quality of life, as measured by the KINDL-R scores on emotional well-being, self-esteem, friends and family, in children and adolescents with ADHD and comorbid ODD/CD. No significant treatment effects were seen on family burden, as measured by FaBel total score.

Jörg Czekalla1, Thomas Wagner2, Alexander Schacht2, Michael Kluge3, Bruce Kinon41Department of Psychiatry and Psychotherapy, RWTH Aachen University, Germany; 2Medical Department, Lilly Deutschland GmbH, Bad Homburg, Germany; 3Max Planck Institute for Clinical Psychiatry, Munich, Germany; 4Lilly Research Laboratories, Indianapolis, USABackground: This study compared effectiveness and acceptance of orally disintegrating olanzapine tablets (ODT) with standard-coated tablets (SOT) in acutely ill psychiatric patients admitted to psychiatric hospitals for emergency treatment.Methods: Large, prospective, observational study at hospital emergency units across Germany in patients with a diagnosis or tentative diagnosis of acute schizophrenia treated with ODT or SOT. Clinical (CGI-S and CGI-I) outcomes, attitudes towards medication (Nursing Assessment of Medication Acceptance, NAMA) scale, suicidal ideation, and adverse events were assessed at start of treatment and after 2 weeks.Results: Both olanzapine formulations, ODT (N = 247) and SOT (N = 207), showed similar effectiveness after 2 weeks. CGI-I improved in 92.1% of patients (ODT: 91.8%, SOT: 92.3%). In patients receiving both formulations suicidal ideations were reduced (ODT from 53.9% to 20.6%, SOT from 51.2% to 22.7%). ODT was preferably given to severely ill (SOT: 49.8%, ODT: 64.4%) and aggressive patients. Adverse events were reported for 6.5% of ODT- and 2.9% of SOT-patients. This difference was possibly caused by the characteristics of patients receiving ODT.Conclusions: This non-randomized, observational study shows comparable outcomes and tolerability in patients treated with both olanzapine formulations. In an acute treatment setting, orally disintegrating tablets were preferably used for more severely ill and aggressive patients with low medication acceptance.Keywords: olanzapine, acute treatment, schizophrenia, observational study

Background The degree of ADHD-related difficulties – reflecting overall impairment, social functioning, and quality of life – may be perceived differently by adolescent patients, parents and physicians. The primary aim of this study was to investigate ADHD-related difficulties during atomoxetine treatment, as perceived by the three different raters. Secondary objectives focused on effectiveness and tolerability of atomoxetine treatment in a population of adolescent patients with ADHD. Methods Adolescents with ADHD, aged 12–17 years, received open-label atomoxetine (0.5–1.2 mg/kg/day) up to 24 weeks. ADHD-related difficulties at various times of the day were rated using the Global Impression of Perceived Difficulties (GIPD) instrument. Inter-rater agreement was analyzed using Cohen's Kappa with 95% confidence intervals (95% CI). ADHD-Rating Scale (ADHD-RS) and Clinical Global Impression Severity (GGI-S) scores were assessed by the investigator; and spontaneous adverse events, vital signs and laboratory parameters were collected for tolerability assessments. Results 159 patients received atomoxetine. Patients' baseline mean GIPD total ratings were significantly lower than parents' and physicians' scores (12.5 [95%CI 11.6;13.5] vs. 17.2 [16.2;18.2] and 18.8 [17.8;19.8]). For all raters, GIPD scores significantly improved over time. Changes were greatest within the first two weeks. Kappa coefficients varied between 0.186 [0.112;0.259] and 0.662 [0.529;0.795], with strongest agreements between parent and physician assessments, and significant improvements of patient/physician agreements over time (based on 95% CIs). ADHD-RS and CGI-S scores significantly improved over the course of the study (based on 95% CIs). Tolerability results were consistent with earlier reports. Conclusion ADHD-related difficulties were perceived differently by the raters in this open-label trial, but consistently improved during atomoxetine treatment. The GIPD instrument appeared sensitive to treatment-related change. These primarily quantitative findings may guide future studies to more systematically investigate the clinical and practical relevance of the differences observed. Additionally, in order to further validate these results, placebo- and comparator-controlled trials are recommended as well as inclusion of healthy controls and other patient populations. Trial Registration Clinical Trial Registry: ClinicalTrials.gov: NCT00191737

Background In many developed countries, the treatment of hyperkinetic disorder (or ADHD) consumes a considerable amount of resources. The primary aim of this study was to determine change in the direct cost of treatment for children and adolescents with hyperkinetic disorder in Germany over time, and compare the cost with the cost of treatment for two physical disorders: epilepsy and asthma. Methods The German Federal Statistical Office provided data on the direct cost of treating hyperkinetic disorder, epilepsy and asthma in Germany for 2002, 2004, and 2006. The direct costs of treatment incurred by hyperkinetic disorder in these years were compared with those incurred by epilepsy and asthma. Results The total direct cost of treatment for the hyperkinetic disorder was € 177 million in 2002, € 234 million in 2004, and € 341 million in 2006. The largest proportion of the cost was incurred by the age group < 15 years: € 158 million in 2002, € 205 million in 2004, and € 287 million in 2006. The direct cost of treatment for epilepsy in this age group was a total of € 157 million in 2002, € 155 million in 2004, and € 155 million in 2006. For asthma, the total direct cost of treatment in this age group was € 266 million in 2002, € 257 million in 2004, and € 272 million in 2006. Conclusion The direct cost of treatment for hyperkinetic disorder in the age group < 15 years increased considerably between 2002 and 2006. Over the same period of time and for the same age group, expenditure for epilepsy and asthma was more or less constant. The increase in expenditure for the treatment of hyperkinetic disorder may be due to increasing demand for diagnostic and therapeutic services and improved availability of such services. The study is limited by the difficulty of obtaining consistent data on the direct cost of treatment for both physical and psychiatric disorders in Germany. peerReviewed

Background Conventional antipsychotics augmented with benzodiazepines have been the standard acute treatment for psychiatric emergencies for more than 50 years. The inability of patients to give informed consent limits randomised, controlled studies. This observational study on immediate therapy for aggression and impulse control in acutely agitated patients (IMPULSE) evaluated the short-term effectiveness and tolerability of atypical and typical antipsychotic medications (AP) in a non-interventional setting. Methods This was a comparative, non-randomised, prospective, open-label, observational study. Treatment over the first 5 days was classified according to whether any olanzapine, risperidone, or haloperidol was included or not. Documentations (PANSS-excited component, CGI-aggression, CGI-suicidality, tranquilisation score) were at baseline (day 1) and days 2–6 after start of AP. Results During the short treatment-period, PANSS-EC and CGI-aggression scores improved in all cohorts. 68.7% of patients treated with olanzapine, 72.2% of patients treated with risperidone, and 83.3% of patients treated with haloperidol received concomitant benzodiazepines (haloperidol vs. non-haloperidol: p < 0.001). More patients treated with olanzapine (73.8%) were fully alert according to a tranquilisation score and active at day 2 than patients treated with risperidone (57.1%) or haloperidol (58.0%). Conclusion Current medication practices for immediate aggression control are effective with positive results present within a few days. In this study, concomitant benzodiazepine use was significantly more frequent in patients receiving haloperidol.

Quality of life (QoL) in patients with schizophrenia has been assessed both from physician and patient perspectives, but little is known about agreement between these perspectives and predictors of agreement. The aim of this study was to analyze a large sample of patients with schizophrenia to discover patterns of physician and patient-rated QoL in patients with schizophrenia and identify predictors for these patterns. This study (EASE) was designed to investigate the QoL and subjective well-being in out-patients with schizophrenia during antipsychotic treatment in a naturalistic setting. Assessments were carried out at baseline and at 3, 6, 9 and 12 months, using the quality of life scale (QLS) and the subjective well-being on neuroleptics scale (SWN-K). A hierarchical cluster analysis was used to define groups of patients based on the SWN-K and QLS total scores at all visits. 1174 patients were included in the cluster analyses that were based on SWN-K and QLS total scores over time. Four distinct clusters were identified: patients with: (1) continuously high QoL (23.2%), (2) continuously moderate QoL (45.8%), (3) continuously low QoL (11.2%), and (4) improving QoL (19.9%). Clusters 1-3 were stable in terms of QoL, whilst cluster 4 changed towards improvement. Various predictors for the four clusters were identified. In the cluster with improving QoL, the absence of treatment with an oral conventional antipsychotic pre-study and no medication change due to lack of efficacy at baseline were predictors for improvement. In the cluster with continuously high QoL, no medication change due to lack of efficacy and lowest CGI-S scores at baseline were predictors. Oral conventional antipsychotic treatment pre-study was predictive for the cluster with continuously moderate QoL. In the cluster with continuously low QoL, medication change due to lack of efficacy and highest CGI-S scores were predictors. These findings suggest that various factors may predict whether a patient with schizophrenia experiences a continuously high QoL, a continuously moderate QoL, a continuously low QoL, or improving QoL whilst on antipsychotic treatment.

Eiji Harada,1 Alexander Schacht,2 Tsukasa Koyama,3 Lauren Marangell,4,5 Toshinaga Tsuji,6 Rodrigo Escobar41Medical Science, Eli Lilly Japan K.K, Kobe, Japan; 2Global Statistical Sciences, Eli Lilly and Company, Bad Homburg, Germany; 3Clinical Research Center, Ohyachi Hospital, Sapporo, Japan; 4Eli Lilly and Company, Indianapolis, IN, 5The University of Texas Health Science Center, Houston, TX, USA; 6Medical Affairs, Shionogi & Co Ltd, Osaka, JapanBackground: Approved doses of antidepressants in Japan are usually lower than those in the USA and European Union, but to date meta-analyses comparing antidepressants have all used the higher doses approved in the USA and European Union and often have used indirect comparisons. The purpose of this study was to conduct an integrated database analysis of patient level data to compare the effects of duloxetine with those of selective serotonin reuptake inhibitors (SSRIs) at the doses approved in Japan.Methods: Pooled data were analyzed from four randomized, double-blind, placebo-controlled studies that compared duloxetine at the dose range approved in Japan (40–60 mg/day) with other SSRIs (paroxetine 20 mg/day or escitalopram 10 mg/day) and placebo in patients with major depressive disorder. In total, 1,694 patients were included in the analysis (duloxetine, n=688; selective serotonin reuptake inhibitors, n=690; placebo, n=316). The primary outcome measure was the mean change from baseline at week 8 in 17-item Hamilton Rating Scale for Depression (HAMD17) total and subscale scores.Results: Duloxetine and both selective serotonin reuptake inhibitors were superior to placebo in HAMD17 total score at week 8 in both the all-randomized group and the more severe subgroup (HAMD17 total scores ≥19). Duloxetine was superior to SSRIs in improving the HAMD17 Retardation subscale score (least squares mean difference [95% confidence interval]): all-randomized group, −0.33 [−0.60, −0.07], P=0.015; severe subgroup, −0.45 [−0.83, −0.07], P=0.020).Conclusion: Within the dose range approved in Japan for patients with major depressive disorder, duloxetine and selective serotonin reuptake inhibitors demonstrated comparable overall efficacy, with a possible advantage for duloxetine in improving loss of energy and interest. To the best of our knowledge, this analysis is unique not only in evaluating dosages specific to Japan, but also in using individual patient data and the same endpoint across studies to allow for strictly direct head-to-head data comparisons as opposed to pooling direct and indirect comparisons.Keywords: duloxetine, selective serotonin reuptake inhibitors, Japan, approved dosage, meta-analysis, major depressive disorder

Antonio Ciudad,1 Ernie Anand,2 Lovisa Berggren,3 Marta Casillas,4 Alexander Schacht,3 Elena Perrin5 1Department of Clinical Research and Development, Eli Lilly & Co, Madrid, Spain; 2Neuroscience Medical Affairs – EU, Lilly Research Centre, Windlesham, Surrey, UK; 3Global Statistical Sciences, Eli Lilly & Co, Bad Homburg, Germany; 4European Scientific Communications, Eli Lilly & Co, Madrid, Spain; 5Medical Department, Eli Lilly & Co, Suresnes, Paris, France Background: A considerable proportion of patients suffering from schizophrenia show suboptimal responses to oral antipsychotics due to inadequate adherence. Hence, they are likely to benefit from switching to a long-acting injectable formulation. These post hoc analyses assessed the clinical effects of switching to olanzapine long-acting injection (OLAI) from either oral olanzapine (OLZ) or other antipsychotics (non-OLZ). Methods: Post hoc analyses were done based on two randomized studies (one short-term, one long-term) conducted in patients suffering from schizophrenia and treated with OLAI. The short-term study was an 8-week placebo-controlled, double-blind trial in acute patients, and the long-term study was a 2-year, oral olanzapine-controlled, open-label, follow-up of stabilized outpatients. Results: These analyses used data from 62 OLAI-treated patients (12 switched from OLZ, 50 from non-OLZ) from the short-term study and 190 OLAI-treated patients (56 switched from OLZ, 134 from non-OLZ) from the long-term study. Kaplan–Meier survival analyses of time to all-cause discontinuation of OLAI treatment did not differ significantly between OLZ and non-OLZ patients in the short-term study (P=0.209) or long-term study (P=0.448). Similarly, the proportions of OLZ and non-OLZ patients that discontinued OLAI were not statistically different in the short-term (16.7% versus 36.0%, respectively; P=0.198) or long-term (57.1% versus 47.8% respectively; P=0.238) studies. In the short-term study, no significant differences were detected between the patient groups in mean change in Positive and Negative Syndrome Scale (PANSS) total score (-13.4 OLZ versus -20.8 non-OLZ; P=0.166). In the long-term study, mean change in PANSS total score (3.9 OLZ versus -3.6 non-OLZ; P=0.008) was significantly different between the non-OLZ and OLZ groups. Rates of treatment-emergent adverse events were similar in OLZ and non-OLZ groups per study. Conclusion: These post hoc analyses suggest that no significant differences in clinical effectiveness were seen after switching from non-OLZ or OLZ to OLAI. However, these findings should be interpreted with care, due to small sample sizes and differences in patients' clinical profiles. Keywords: schizophrenia, olanzapine, long-acting injection, depot formulation

Sensory profiles are heterogeneous in neuropathic pain disorders, and subgroups of patients respond differently to treatment. To further explore this, patients in the COMBO-DN study were prospectively assessed by the Neuropathic Pain Symptom Inventory (NPSI) at baseline, after initial 8-week therapy with either duloxetine or pregabalin, and after subsequent 8-week combination/high-dose therapy. Exploratory post hoc cluster analyses were performed to identify and characterize potential subgroups through their scores in the NPSI items. In patients not responding to initial 60mg/d duloxetine, adding 300mg/d pregabalin for combination treatment was particularly effective regarding the dimensions pressing pain and evoked pain, whereas maximizing the duloxetine dose to 120mg/d appeared more beneficial regarding paresthesia/dysesthesia. In contrast, adding 60mg/d duloxetine to 300mg/d pregabalin in case of nonresponse to initial pregabalin led to numerically higher decreases in all NPSI dimensions/items compared to maximizing the pregabalin dose to 600mg/d. Cluster analysis revealed 3 patient clusters (defined by baseline scores for the 10 NPSI sensory items) with different pain profiles, not only in terms of overall pain severity, but also across NPSI items. Mean Brief Pain Inventory average pain improved in all clusters during combination/high-dose therapy. However, in patients with severe pain, the treatment effect showed a trend in favor of high-dose monotherapy, whereas combination therapy appeared to be more beneficial in patients with moderate and mild pain (not significant). These complementary exploratory analyses further endorse the idea that sensory phenotyping might lead to a more stratified treatment and potentially to personalized pain therapy.