Showing papers on "Placebo published in 2014"

Pharmacological interventions for somatoform disorders in adults.

Abstract: BACKGROUND: Somatoform disorders are characterised by chronic, medically unexplained physical symptoms (MUPS). Although different medications are part of treatment routines for people with somatoform disorders in clinics and private practices, there exists no systematic review or meta-analysis on the efficacy and tolerability of these medications. We aimed to synthesise to improve optimal treatment decisions.OBJECTIVES: To assess the effects of pharmacological interventions for somatoform disorders (specifically somatisation disorder, undifferentiated somatoform disorder, somatoform autonomic dysfunction, and pain disorder) in adults.SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR) (to 17 January 2014). This register includes relevant randomised controlled trials (RCTs) from The Cochrane Library (all years), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to date). To identify ongoing trials, we searched ClinicalTrials.gov, Current Controlled Trials metaRegister, the World Health Organization International Clinical Trials Registry Platform, and the Chinese Clinical Trials Registry. For grey literature, we searched ProQuest Dissertation {\&} Theses Database, OpenGrey, and BIOSIS Previews. We handsearched conference proceedings and reference lists of potentially relevant papers and systematic reviews and contacted experts in the field.SELECTION CRITERIA: We selected RCTs or cluster RCTs of pharmacological interventions versus placebo, treatment as usual, another medication, or a combination of different medications for somatoform disorders in adults. We included people fulfilling standardised diagnostic criteria for somatisation disorder, undifferentiated somatoform disorder, somatoform autonomic dysfunction, or somatoform pain disorder.DATA COLLECTION AND ANALYSIS: One review author and one research assistant independently extracted data and assessed risk of bias. Primary outcomes included the severity of MUPS on a continuous measure, and acceptability of treatment.MAIN RESULTS: We included 26 RCTs (33 reports), with 2159 participants, in the review. They examined the efficacy of different types of antidepressants, the combination of an antidepressant and an antipsychotic, antipsychotics alone, or natural products (NPs). The duration of the studies ranged between two and 12 weeks.One meta-analysis of placebo-controlled studies showed no clear evidence of a significant difference between tricyclic antidepressants (TCAs) and placebo for the outcome severity of MUPS (SMD -0.13; 95{\%} CI -0.39 to 0.13; 2 studies, 239 participants; I(2) = 2{\%}; low-quality evidence). For new-generation antidepressants (NGAs), there was very low-quality evidence showing they were effective in reducing the severity of MUPS (SMD -0.91; 95{\%} CI -1.36 to -0.46; 3 studies, 243 participants; I(2) = 63{\%}). For NPs there was low-quality evidence that they were effective in reducing the severity of MUPS (SMD -0.74; 95{\%} CI -0.97 to -0.51; 2 studies, 322 participants; I(2) = 0{\%}).One meta-analysis showed no clear evidence of a difference between TCAs and NGAs for severity of MUPS (SMD -0.16; 95{\%} CI -0.55 to 0.23; 3 studies, 177 participants; I(2) = 42{\%}; low-quality evidence). There was also no difference between NGAs and other NGAs for severity of MUPS (SMD -0.16; 95{\%} CI -0.45 to 0.14; 4 studies, 182 participants; I(2) = 0{\%}).Finally, one meta-analysis comparing selective serotonin reuptake inhibitors (SSRIs) with a combination of SSRIs and antipsychotics showed low-quality evidence in favour of combined treatment for severity of MUPS (SMD 0.77; 95{\%} CI 0.32 to 1.22; 2 studies, 107 participants; I(2) = 23{\%}).Differences regarding the acceptability of the treatment (rate of all-cause drop-outs) were neither found between NGAs and placebo (RR 1.01, 95{\%} CI 0.64 to 1.61; 2 studies, 163 participants; I(2) = 0{\%}; low-quality evidence) or NPs and placebo (RR 0.85, 95{\%} CI 0.40 to 1.78; 3 studies, 506 participants; I(2) = 0{\%}; low-quality evidence); nor between TCAs and other medication (RR 1.48, 95{\%} CI 0.59 to 3.72; 8 studies, 556 participants; I(2) =14{\%}; low-quality evidence); nor between antidepressants and the combination of an antidepressant and an antipsychotic (RR 0.80, 95{\%} CI 0.25 to 2.52; 2 studies, 118 participants; I(2) = 0{\%}; low-quality evidence). Percental attrition rates due to adverse effects were high in all antidepressant treatments (0{\%} to 32{\%}), but low for NPs (0{\%} to 1.7{\%}).The risk of bias was high in many domains across studies. Seventeen trials (65.4{\%}) gave no information about random sequence generation and only two (7.7{\%}) provided information about allocation concealment. Eighteen studies (69.2{\%}) revealed a high or unclear risk in blinding participants and study personnel; 23 studies had high risk of bias relating to blinding assessors. For the comparison NGA versus placebo, there was relatively high imprecision and heterogeneity due to one outlier study. Although we identified 26 studies, each comparison only contained a few studies and small numbers of participants so the results were imprecise.AUTHORS' CONCLUSIONS: The current review found very low-quality evidence for NGAs and low-quality evidence for NPs being effective in treating somatoform symptoms in adults when compared with placebo. There was some evidence that different classes of antidepressants did not differ in efficacy; however, this was limited and of low to very low quality. These results had serious shortcomings such as the high risk of bias, strong heterogeneity in the data, and small sample sizes. Furthermore, the significant effects of antidepressant treatment have to be balanced against the relatively high rates of adverse effects. Adverse effects produced by medication can have amplifying effects on symptom perceptions, particularly in people focusing on somatic symptoms without medical causes. We can only draw conclusions about short-term efficacy of the pharmacological interventions because no trial included follow-up assessments. For each of the comparisons where there were available data on acceptability rates (NGAs versus placebo, NPs versus placebo, TCAs versus other medication, and antidepressants versus a combination of an antidepressant and an antipsychotic), no clear differences between the intervention and comparator were found.Future high-quality research should be carried out to determine the effectiveness of medications other than antidepressants, to compare antidepressants more thoroughly, and to follow-up participants over longer periods (the longest follow up was just 12 weeks). Another idea for future research would be to include other outcomes such as functional impairment or dysfunctional behaviours and cognitions as well as the classical outcomes such as symptom severity, depression, or anxiety.

Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma

Abstract: BACKGROUND: Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids. METHODS: In this randomized, double-blind, double-dummy study, we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups. Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5, which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, or placebo every 4 weeks for 32 weeks. The primary outcome was the rate of exacerbations. Other outcomes included the forced expiratory volume in 1 second (FEV1) and scores on the St. George's Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5). Safety was also assessed. RESULTS: The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32% in the group receiving intravenous mepolizumab and by 61% in the group receiving subcutaneous mepolizumab. At week 32, the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo (P=0.02) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo (P=0.03). The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 4 points), and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 0.5 points) (P<0.001 for all comparisons). The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS: Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control. (Funded by GlaxoSmithKline; MENSA ClinicalTrials.gov number, NCT01691521.).

Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial

Abstract: BACKGROUND: Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy. METHODS: We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614. FINDINGS: From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11.2 months (95% CI 9.5-12.7) with ipilimumab and 10.0 months (8.3-11.0) with placebo (hazard ratio [HR] 0.85, 0.72-1.00; p=0.053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0.0031). A piecewise hazard model showed that the HR changed over time: the HR for 0-5 months was 1.46 (95% CI 1.10-1.95), for 5-12 months was 0.65 (0.50-0.85), and beyond 12 months was 0.60 (0.43-0.86). The most common grade 3-4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3-4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group. INTERPRETATION: Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation. FUNDING: Bristol-Myers Squibb.

Fibrinolysis for Patients with Intermediate- Risk Pulmonary Embolism

Abstract: BACKGROUND: The role of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism is controversial. METHODS: In a randomized, double-blind trial, we compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk pulmonary embolism. Eligible patients had right ventricular dysfunction on echocardiography or computed tomography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T. The primary outcome was death or hemodynamic decompensation (or collapse) within 7 days after randomization. The main safety outcomes were major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization. RESULTS: Of 1006 patients who underwent randomization, 1005 were included in the intention-to-treat analysis. Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P=0.02). Between randomization and day 7, a total of 6 patients (1.2%) in the tenecteplase group and 9 (1.8%) in the placebo group died (P=0.42). Extracranial bleeding occurred in 32 patients (6.3%) in the tenecteplase group and 6 patients (1.2%) in the placebo group (P<0.001). Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was hemorrhagic (P=0.003). By day 30, a total of 12 patients (2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P=0.42). CONCLUSIONS: In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke. (Funded by the Programme Hospitalier de Recherche Clinique in France and others; PEITHO EudraCT number, 2006-005328-18; ClinicalTrials.gov number, NCT00639743.).

Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.

Abstract: BACKGROUND Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has shown efficacy in patients with asthma and elevated eosinophil levels. The blockade by dupilumab of these key drivers of type 2 helper T-cell (Th2)–mediated inflammation could help in the treatment of related diseases, including atopic dermatitis. METHODS We performed randomized, double-blind, placebo-controlled trials involving adults who had moderate-to-severe atopic dermatitis despite treatment with topical glucocorticoids and calcineurin inhibitors. Dupilumab was evaluated as monotherapy in two 4-week trials and in one 12-week trial and in combination with topical glucocorticoids in another 4-week study. End points included the Eczema Area and Severity Index (EASI) score, the investigator’s global assessment score, pruritus, safety assessments, serum biomarker levels, and disease transcriptome. RESULTS In the 4-week monotherapy studies, dupilumab resulted in rapid and dose-dependent improvements in clinical indexes, biomarker levels, and the transcriptome. The results of the 12-week study of dupilumab monotherapy reproduced and extended the 4-week findings: 85% of patients in the dupilumab group, as compared with 35% of those in the placebo group, had a 50% reduction in the EASI score (EASI-50, with higher scores in the EASI indicating greater severity of eczema) (P<0.001); 40% of patients in the dupilumab group, as compared with 7% in the placebo group, had a score of 0 to 1 (indicating clearing or near-clearing of skin lesions) on the investigator’s global assessment (P<0.001); and pruritus scores decreased (indicating a reduction in itch) by 55.7% in the dupilumab group versus 15.1% in the placebo group (P<0.001). In the combination study, 100% of the patients in the dupilumab group, as compared with 50% of those who received topical glucocorticoids with placebo injection, met the criterion for EASI-50 (P = 0.002), despite the fact that patients who received dupilumab plus glucocorticoids used less than half the amount of topical glucocorticoids used by those who received placebo plus the topical medication (P = 0.16). Adverse events, such as skin infection, occurred more frequently with placebo; nasopharyngitis and headache were the most frequent adverse events with dupilumab. CONCLUSIONS Patients treated with dupilumab had marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity. Side-effect profiles were not doselimiting. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT01259323, NCT01385657, NCT01639040, and NCT01548404.)

Selexipag for the treatment of pulmonary arterial hypertension.

Abstract: BackgroundIn a phase 2 trial, selexipag, an oral selective IP prostacyclin-receptor agonist, was shown to be beneficial in the treatment of pulmonary arterial hypertension. MethodsIn this event-driven, phase 3, randomized, double-blind, placebo-controlled trial, we randomly assigned 1156 patients with pulmonary arterial hypertension to receive placebo or selexipag in individualized doses (maximum dose, 1600 μg twice daily). Patients were eligible for enrollment if they were not receiving treatment for pulmonary arterial hypertension or if they were receiving a stable dose of an endothelin-receptor antagonist, a phosphodiesterase type 5 inhibitor, or both. The primary end point was a composite of death from any cause or a complication related to pulmonary arterial hypertension up to the end of the treatment period (defined for each patient as 7 days after the date of the last intake of selexipag or placebo). ResultsA primary end-point event occurred in 397 patients — 41.6% of those in the placebo group and...

Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials.

Abstract: with depression (SMD, −0.54; 95% CI, −1.08 to −0.01; I 2 = 68%) and depressive symptoms (SMD, −0.27; 95% CI, −0.53 to −0.01; I 2 = 68%). The heterogeneity of the studies was not explained by differences in inclusion of clinical depression vs depressive symptoms or use of NSAIDs vs cytokine inhibitors. Subanalyses emphasized the antidepressant properties of the selective cyclooxygenase 2 inhibitor celecoxib (SMD, −0.29; 95% CI, −0.49 to −0.08; I 2 =7 3%) on remission (OR, 7.89; 95% CI, 2.94 to 21.17; I 2 = 0%) and response (OR, 6.59; 95% CI, 2.24 to 19.42; I 2 = 0%). Among the 6 studies reporting on adverse effects, we found no evidence of an increased number of gastrointestinal or cardiovascular events after 6 weeks or infections after 12 weeks of anti-inflammatory treatment compared with placebo. All trials were associated with a high risk of bias owing to potentially compromised internal validity.

Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial

Abstract: Summary Background Panobinostat is a potent oral pan-deacetylase inhibitor that in preclinical studies has synergistic anti-myeloma activity when combined with bortezomib and dexamethasone. We aimed to compare panobinostat, bortezomib, and dexamethasone with placebo, bortezomib, and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma. Methods PANORAMA1 is a multicentre, randomised, placebo-controlled, double-blind phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma who have received between one and three previous treatment regimens. Patients were randomly assigned (1:1) via an interactive web-based and voice response system, stratified by number of previous treatment lines and by previous use of bortezomib, to receive 21 day cycles of placebo or panobinostat (20 mg; on days 1, 3, 5, 8, 10, 12, orally), both in combination with bortezomib (1·3 mg/m 2 on days 1, 4, 8, 11, intravenously) and dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, 12, orally). Patients, physicians, and the investigators who did the data analysis were masked to treatment allocation; crossover was not permitted. The primary endpoint was progression-free survival (in accordance with modified European Group for Blood and Marrow Transplantation criteria and based on investigators' assessment) and was analysed by intention to treat. The study is ongoing, but no longer recruiting, and is registered at ClinicalTrials.gov, number NCT01023308. Findings 768 patients were enrolled between Jan 21, 2010, and Feb 29, 2012, with 387 randomly assigned to panobinostat, bortezomib, and dexamethasone and 381 to placebo, bortezomib, and dexamethasone. Median follow-up was 6·47 months (IQR 1·81–13·47) in the panobinostat group and 5·59 months (2·14–11·30) in the placebo group. Median progression-free survival was significantly longer in the panobinostat group than in the placebo group (11·99 months [95% CI 10·33–12·94] vs 8·08 months [7·56–9·23]; hazard ratio [HR] 0·63, 95% CI 0·52–0·76; p vs 208 [54·6%, 49·4–59·7] for placebo; p=0·09); however, the proportion of patients with a complete or near complete response was significantly higher in the panobinostat group than in the placebo group (107 [27·6%, 95% CI 23·2–32·4] vs 60 [15·7%, 12·2–19·8]; p=0·00006). Minimal responses were noted in 23 (6%) patients in the panobinostat group and in 42 (11%) in the placebo group. Median duration of response (partial response or better) was 13·14 months (95% CI 11·76–14·92) in the panobinostat group and 10·87 months (9·23–11·76) in the placebo group, and median time to response (partial response or better) was 1·51 months (1·41–1·64) in the panobinostat group and 2·00 months (1·61–2·79) in the placebo group. Serious adverse events were reported in 228 (60%) of 381 patients in the panobinostat group and 157 (42%) of 377 patients in the placebo group. Common grade 3–4 laboratory abnormalities and adverse events (irrespective of association with study drug) included thrombocytopenia (256 [67%] in the panobinostat group vs 118 [31%] in the placebo group), lymphopenia (202 [53%] vs 150 [40%]), diarrhoea (97 [26%] vs 30 [8%]), asthenia or fatigue (91 [24%] vs 45 [12%]), and peripheral neuropathy (67 [18%] vs 55 [15%]). Interpretation Our results suggest that panobinostat could be a useful addition to the treatment armamentarium for patients with relapsed or relapsed and refractory multiple myeloma. Longer follow up will be necessary to determine whether there is any effect on overall survival. Funding Novartis Pharmaceuticals.

Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study.

Abstract: Summary Background Levodopa is the most effective therapy for Parkinson's disease, but chronic treatment is associated with the development of potentially disabling motor complications. Experimental studies suggest that motor complications are due to non-physiological, intermittent administration of the drug, and can be reduced with continuous delivery. We aimed to assess efficacy and safety of levodopa-carbidopa intestinal gel delivered continuously through an intrajejunal percutaneous tube. Methods In our 12-week, randomised, double-blind, double-dummy, double-titration trial, we enrolled adults (aged ≥30 years) with advanced Parkinson's disease and motor complications at 26 centres in Germany, New Zealand, and the USA. Eligible participants had jejunal placement of a percutaneous gastrojejunostomy tube, and were then randomly allocated (1:1) to treatment with immediate-release oral levodopa-carbidopa plus placebo intestinal gel infusion or levodopa-carbidopa intestinal gel infusion plus oral placebo. Randomisation was stratified by site, with a mixed block size of 2 or 4. The primary endpoint was change from baseline to final visit in motor off-time. We assessed change in motor on-time without troublesome dyskinesia as a prespecified key secondary outcome. We assessed efficacy in a full-analysis set of participants with data for baseline and at least one post-baseline assessment, and imputed missing data with the last observation carried forward approach. We assessed safety in randomly allocated patients who underwent the percutaneous gastrojejunostomy procedure. This study is registered with ClinicalTrials.gov, numbers NCT00660387 and NCT0357994. Findings From baseline to 12 weeks in the full-analysis set, mean off-time decreased by 4·04 h (SE 0·65) for 35 patients allocated to the levodopa-carbidopa intestinal gel group compared with a decrease of 2·14 h (0·66) for 31 patients allocated to immediate-release oral levodopa-carbidopa (difference −1·91 h [95% CI −3·05 to −0·76]; p=0·0015). Mean on-time without troublesome dyskinesia increased by 4·11 h (SE 0·75) in the intestinal gel group and 2·24 h (0·76) in the immediate-release oral group (difference 1·86 [95% CI 0·56 to 3·17]; p=0·0059). In the safety analyses 35 (95%) of 37 patients allocated to the levodopa-carbidopa intestinal gel group had adverse events (five [14%] serious), as did 34 (100%) of 34 patients allocated to the immediate-release oral levodopa-carbidopa group (seven [21%] serious), mainly associated with the percutaneous gastrojejunostomy tube. Interpretation Continuous delivery of levodopa-carbidopa with an intestinal gel offers a promising option for control of advanced Parkinson's disease with motor complications. Benefits noted with intestinal gel delivery were of a greater magnitude than were those obtained with medical therapies to date, and our study is, to our knowledge, the first demonstration of the benefit of continuous levodopa delivery in a double-blind controlled study. Funding AbbVie.

Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial.

Abstract: RESULTS No significant difference in overall survival was seen between treatment groups, with 303 deaths (83.7%) in the everolimus group and 151 deaths (82.1%) in the placebo group (hazard ratio [HR], 1.05; 95% CI, 0.86-1.27; P = .68; median overall survival, 7.6 months with everolimus, 7.3 months with placebo). Median time to progression with everolimus and placebo was 3.0 months and 2.6 months, respectively (HR, 0.93; 95% CI, 0.75-1.15), and disease control rate was 56.1% and 45.1%, respectively (P = .01). The most common grade 3/4 adverse events for everolimus vs placebo were anemia (7.8% vs 3.3%, respectively), asthenia (7.8% vs 5.5%, respectively), and decreased appetite (6.1% vs 0.5%, respectively). No patients experienced hepatitis C viral flare. Based on central laboratory results, hepatitis B viral reactivation was experienced by 39 patients (29 everolimus, 10 placebo); all cases were asymptomatic, but 3 everolimus recipients discontinued therapy.

Omalizumab for asthma in adults and children.

Abstract: Background Asthma is a respiratory (airway) condition that affects an estimated 300 million people worldwide and is associated with significant morbidity and mortality. Omalizumab is a monoclonal antibody that binds and inhibits free serum immunoglobulin E (IgE). It is called an 'anti-IgE' drug. IgE is an immune mediator involved in clinical manifestations of asthma. A recent update of National Institute for Health and Care Excellence (NICE) guidance in 2013 recommends omalizumab for use as add-on therapy in adults and children over six years of age with inadequately controlled severe persistent allergic IgE-mediated asthma who require continuous or frequent treatment with oral corticosteroids. Objectives To assess the effects of omalizumab versus placebo or conventional therapy for asthma in adults and children. Search methods We searched the Cochrane Airways Group Specialised Register of trials for potentially relevant studies. The most recent search was performed in June 2013. We also checked the reference lists of included trials and searched online trial registries and drug company websites. Selection criteria Randomised controlled trials examining anti-IgE administered in any manner for any duration. Trials with co-interventions were included, as long as they were the same in each arm. Data collection and analysis Two review authors independently assessed study quality and extracted and entered data. Three modes of administration were identified from the published literature: inhaled, intravenous and subcutaneous injection. The main focus of the updated review is subcutaneous administration, as this route is currently used in clinical practice. Subgroup analysis was performed by asthma severity. Data were extracted from published and unpublished sources. Main results In all, 25 trials were included in the review, including 11 new studies since the last update, for a total of 19 that considered the efficacy of subcutaneous anti-IgE treatment as an adjunct to treatment with corticosteroids. For participants with moderate or severe asthma who were receiving background inhaled corticosteroid steroid (ICS) therapy, a significant advantage favoured subcutaneous omalizumab with regard to experiencing an asthma exacerbation (odds ratio (OR) 0.55, 95% confidence interval (CI) 0.42 to 0.60; ten studies, 3261 participants). This represents an absolute reduction from 26% for participants suffering an exacerbation on placebo to 16% on omalizumab, over 16 to 60 weeks. A significant benefit was noted for subcutaneous omalizumab versus placebo with regard to reducing hospitalisations (OR 0.16, 95% CI 0.06 to 0.42; four studies, 1824 participants), representing an absolute reduction in risk from 3% with placebo to 0.5% with omalizumab over 28 to 60 weeks. No separate data on hospitalisations were available for the severe asthma subgroup, and all of these data were reported for participants with the diagnosis of moderate to severe asthma. Participants treated with subcutaneous omalizumab were also significantly more likely to be able to withdraw their ICS completely than those treated with placebo (OR 2.50, 95% CI 2.00 to 3.13), and a small but statistically significant reduction in daily inhaled steroid dose was reported for omalizumab-treated participants compared with those given placebo (weighted mean difference (WMD) -118 mcg beclomethasone dipropionate (BDP) equivalent per day, 95% CI -154 to -84). However, no significant difference between omalizumab and placebo treatment groups was seen in the number of participants who were able to withdraw from oral corticosteroid (OCS) therapy (OR 1.18, 95% CI 0.53 to 2.63). Participants treated with subcutaneous omalizumab as an adjunct to treatment with corticosteroids required a small but significant reduction in rescue beta2-agonist medication compared with placebo (mean difference (MD) -0.39 puffs per day, 95% CI -0.55 to -0.24; nine studies, 3524 participants). This benefit was observed in both the moderate to severe (MD -0.58, 95% CI -0.84 to -0.31) and severe (MD -0.30, 95% CI -0.49 to -0.10) asthma subgroups on a background therapy of inhaled corticosteroids; however, no significant difference between subcutaneous omalizumab and placebo was noted for this outcome in participants with severe asthma who were receiving a background therapy of inhaled plus oral corticosteroids. Significantly fewer serious adverse events were reported in participants assigned to subcutaneous omalizumab than in those receiving placebo (OR 0.72, 95% CI 0.57 to 0.91; 15 studies, 5713 participants), but more injection site reactions were observed (from 5.6% with placebo to 9.1% with omalizumab). To reflect current clinical practice, discussion of the results is limited to subcutaneous use, and trials involving intravenous and inhaled routes have been archived. Authors' conclusions Omalizumab was effective in reducing asthma exacerbations and hospitalisations as an adjunctive therapy to inhaled steroids and during steroid tapering phases of clinical trials. Omalizumab was significantly more effective than placebo in increasing the numbers of participants who were able to reduce or withdraw their inhaled steroids. Omalizumab was generally well tolerated, although more injection site reactions were seen with omalizumab. Further assessment in paediatric populations is necessary, as is direct double-dummy comparison with ICS. Although subgroup analyses suggest that participants receiving prednisolone had better asthma control when they received omalizumab, it remains to be tested prospectively whether the addition of omalizumab has a prednisolone-sparing effect. It is also not clear whether there is a threshold level of baseline serum IgE for optimum efficacy of omalizumab. Given the high cost of the drug, identification of biomarkers predictive of response is of major importance for future research.

Over-the-counter medications for acute cough in children and adults in ambulatory settings.

Abstract: Background Acute cough due to upper respiratory tract infection (URTI) is a common symptom. Non-prescription, over-the-counter (OTC) medicines are frequently recommended as a first-line treatment, but there is little evidence as to whether these drugs are effective. Objectives To assess the effects of oral OTC cough preparations for acute cough in children and adults in community settings. Search methods We searched CENTRAL (2014, Issue 1), MEDLINE (January 1966 to March week 3 2014), EMBASE (January 1974 to March 2014), CINAHL (January 2010 to March 2014), LILACS (January 2010 to March 2014), Web of Science (January 2010 to March 2014) and the UK Department of Health National Research Register (March 2010). Selection criteria Randomised controlled trials (RCTs) comparing oral OTC cough preparations with placebo in children and adults suffering from acute cough in community settings. We considered all cough outcomes; secondary outcomes of interest were adverse effects. Data collection and analysis Two review authors independently screened potentially relevant citations, extracted data and assessed study quality. We performed quantitative analysis where appropriate. Main results Due to the small numbers of trials in each category, the limited quantitative data available and the marked differences between trials in terms of participants, interventions and outcome measurement, we felt that pooling of the results was inappropriate. We included 29 trials (19 in adults, 10 in children) involving 4835 people (3799 adults and 1036 children). All studies were placebo-controlled RCTs. However, assessment of the risk of bias of the included studies was limited by poor reporting, particularly for the earlier studies. In the adult studies, six trials compared antitussives with placebo and had variable results. Three trials compared the expectorant guaifenesin with placebo; one indicated significant benefit, whereas the other two did not. One trial found that a mucolytic reduced cough frequency and symptom scores. Two studies examined antihistamine-decongestant combinations and found conflicting results. Four studies compared other combinations of drugs with placebo and indicated some benefit in reducing cough symptoms. Three trials found that antihistamines were no more effective than placebo in relieving cough symptoms. In the child studies, antitussives (data from three studies), antihistamines (data from three studies), antihistamine-decongestants (two studies) and antitussive/bronchodilator combinations (one study) were no more effective than placebo. No studies using expectorants met our inclusion criteria. The results of one trial favoured active treatment with mucolytics over placebo. One trial tested two paediatric cough syrups and both preparations showed a 'satisfactory response' in 46% and 56% of children compared to 21% of children in the placebo group. One new trial indicated that three types of honey were more effective than placebo over a three-day period. Twenty-one studies reported adverse effects. There was a wide range across studies, with higher numbers of adverse effects in participants taking preparations containing antihistamines and dextromethorphan. Authors' conclusions The results of this review have to be interpreted with caution because the number of studies in each category of cough preparations was small. Availability, dosing and duration of use of over-the-counter cough medicines vary significantly in different countries. Many studies were poorly reported making assessment of risk of bias difficult and studies were also very different from each other, making evaluation of overall efficacy difficult. There is no good evidence for or against the effectiveness of OTC medicines in acute cough. This should be taken into account when considering prescribing antihistamines and centrally active antitussive agents in children; drugs that are known to have the potential to cause serious harm.

Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease The TEAM-AD VA Cooperative Randomized Trial

Abstract: Importance Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD. Objective To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor. Design, Setting, and Participants Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers. Interventions Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152). Main Outcomes and Measures Alzheimer’s Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures. Results Data from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, −0.24 to 4.20; adjusted P = .40) than the placebo group’s decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of “infections or infestations,” with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants). Conclusions and Relevance Among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden. Trial Registration clinicaltrials.gov Identifier:NCT00235716

Effect of Citalopram on Agitation in Alzheimer Disease: The CitAD Randomized Clinical Trial

Abstract: Importance Agitation is common, persistent, and associated with adverse consequences for patients with Alzheimer disease. Pharmacological treatment options, including antipsychotics are not satisfactory. Objective The primary objective was to evaluate the efficacy of citalopram for agitation in patients with Alzheimer disease. Key secondary objectives examined effects of citalopram on function, caregiver distress, safety, cognitive safety, and tolerability. Design, Setting, and Participants The Citalopram for Agitation in Alzheimer Disease Study (CitAD) was a randomized, placebo-controlled, double-blind, parallel group trial that enrolled 186 patients with probable Alzheimer disease and clinically significant agitation from 8 academic centers in the United States and Canada from August 2009 to January 2013. Interventions Participants (n = 186) were randomized to receive a psychosocial intervention plus either citalopram (n = 94) or placebo (n = 92) for 9 weeks. Dosage began at 10 mg per day with planned titration to 30 mg per day over 3 weeks based on response and tolerability. Main Outcomes and Measures Primary outcome measures were based on scores from the 18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC). Other outcomes were based on scores from the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory (NPI), ability to complete activities of daily living (ADLs), caregiver distress, cognitive safety (based on scores from the 30-point Mini Mental State Examination [MMSE]), and adverse events. Results Participants who received citalopram showed significant improvement compared with those who received placebo on both primary outcome measures. The NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was −0.93 (95% CI, −1.80 to −0.06), P = .04. Results from the mADCS-CGIC showed 40% of citalopram participants having moderate or marked improvement from baseline compared with 26% of placebo recipients, with estimated treatment effect (odds ratio [OR] of being at or better than a given CGIC category) of 2.13 (95% CI, 1.23-3.69), P = .01. Participants who received citalopram showed significant improvement on the CMAI, total NPI, and caregiver distress scores but not on the NPI agitation subscale, ADLs, or in less use of rescue lorazepam. Worsening of cognition (−1.05 points; 95% CI, −1.97 to −0.13; P = .03) and QT interval prolongation (18.1 ms; 95% CI, 6.1-30.1; P = .01) were seen in the citalopram group. Conclusions and Relevance Among patients with probable Alzheimer disease and agitation who were receiving psychosocial intervention, the addition of citalopram compared with placebo significantly reduced agitation and caregiver distress; however, cognitive and cardiac adverse effects of citalopram may limit its practical application at the dosage of 30 mg per day. Trial Registration clinicaltrials.gov Identifier:NCT00898807

Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis

Abstract: Background Opioids can increase sensitivity to noxious stimuli and cause opioid-induced hyperalgesia. We performed a systematic review to evaluate the clinical consequences of intra-operative doses of opioid. Methods We identified randomized controlled trials which compared intra-operative opioid to lower doses or placebo in adult patients undergoing surgery from MEDLINE, EMBASE, LILAC, Cochrane, and hand searches of trial registries. We pooled data of postoperative pain intensity, morphine consumption, incidence of opioid-related side-effects, primary and secondary hyperalgesia. For dichotomous outcomes relative risks [95% confidence intervals (CIs)] and for continuous outcomes mean differences (MDs) or standardized mean difference (SMD; 95% CI) were calculated. Results Twenty-seven studies involving 1494 patients were included in the analysis. Patients treated with high intra-operative doses of opioid reported higher postoperative pain intensity than the reference groups (MD: 9.4 cm; 95% CI: 4.4, 14.5) at 1 h, (MD: 7.1 cm; 95% CI: 2.8, 11.3) at 4 h, and (MD: 3 cm; 95% CI: 0.4, 5.6) at 24 h on a 100 cm visual analogue scale. They also showed higher postoperative morphine use after 24 h (SMD: 0.7; 95% CI: 0.37, 1.02). There was no difference in the incidences of nausea, vomiting, and drowsiness. These results were mainly associated with the use of remifentanil. The impact of other opioids is less clear because of limited data. Discussion This review suggests that high intra-operative doses of remifentanil are associated with small but significant increases in acute pain after surgery.

Very Early Administration of Progesterone for Acute Traumatic Brain Injury

Abstract: BACKGROUND Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Progesterone has been shown to improve neurologic outcome in multiple experimental models and two early-phase trials involving patients with TBI. METHODS We conducted a double-blind, multicenter clinical trial in which patients with severe, moderate-to-severe, or moderate acute TBI (Glasgow Coma Scale score of 4 to 12, on a scale from 3 to 15, with lower scores indicating a lower level of consciousness) were randomly assigned to intravenous progesterone or placebo, with the study treatment initiated within 4 hours after injury and administered for a total of 96 hours. Efficacy was defined as an increase of 10 percentage points in the proportion of patients with a favorable outcome, as determined with the use of the stratified dichotomy of the Extended Glasgow Outcome Scale score at 6 months after injury. Secondary outcomes included mortality and the Disability Rating Scale score. RESULTS A total of 882 of the planned sample of 1140 patients underwent randomization before the trial was stopped for futility with respect to the primary outcome. The study groups were similar with regard to baseline characteristics; the median age of the patients was 35 years, 73.7% were men, 15.2% were black, and the mean Injury Severity Score was 24.4 (on a scale from 0 to 75, with higher scores indicating greater severity). The most frequent mechanism of injury was a motor vehicle accident. There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P = 0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes. CONCLUSIONS This clinical trial did not show a benefit of progesterone over placebo in the improvement of outcomes in patients with acute TBI. (Funded by the National Institute of Neurological Disorders and Stroke and others; PROTECT III ClinicalTrials.gov number, NCT00822900.)

Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial

Abstract: Summary Background Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases. Methods In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov, number NCT00699751. Findings Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months [95% CI 13·5–18·0] vs 9·8 months [7·3–23·7]; hazard ratio [HR]=0·66, 95% CI 0·52–0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53–0·85) and spinal cord compression (HR=0·52, 95% CI 0·29–0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35–1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28–1·82). Interpretation Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases. Funding Algeta and Bayer HealthCare Pharmaceuticals.

Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia.

Abstract: Background Duloxetine is a balanced serotonin and noradrenaline reuptake inhibitor licensed for the treatment of major depressive disorders, urinary stress incontinence and the management of neuropathic pain associated with diabetic peripheral neuropathy. A number of trials have been conducted to investigate the use of duloxetine in neuropathic and nociceptive painful conditions. This is the first update of a review first published in 2010. Objectives To assess the benefits and harms of duloxetine for treating painful neuropathy and different types of chronic pain. Search methods On 19th November 2013, we searched The Cochrane Neuromuscular Group Specialized Register, CENTRAL, DARE, HTA, NHSEED, MEDLINE, and EMBASE. We searched ClinicalTrials.gov for ongoing trials in April 2013. We also searched the reference lists of identified publications for trials of duloxetine for the treatment of painful peripheral neuropathy or chronic pain. Selection criteria We selected all randomised or quasi-randomised trials of any formulation of duloxetine, used for the treatment of painful peripheral neuropathy or chronic pain in adults. Data collection and analysis We used standard methodological procedures expected by The Cochrane Collaboration. Main results We identified 18 trials, which included 6407 participants. We found 12 of these studies in the literature search for this update. Eight studies included a total of 2728 participants with painful diabetic neuropathy and six studies involved 2249 participants with fibromyalgia. Three studies included participants with depression and painful physical symptoms and one included participants with central neuropathic pain. Studies were mostly at low risk of bias, although significant drop outs, imputation methods and almost every study being performed or sponsored by the drug manufacturer add to the risk of bias in some domains. Duloxetine at 60 mg daily is effective in treating painful diabetic peripheral neuropathy in the short term, with a risk ratio (RR) for ≥ 50% pain reduction at 12 weeks of 1.73 (95% CI 1.44 to 2.08). The related NNTB is 5 (95% CI 4 to 7). Duloxetine at 60 mg daily is also effective for fibromyalgia over 12 weeks (RR for ≥ 50% reduction in pain 1.57, 95% CI 1.20 to 2.06; NNTB 8, 95% CI 4 to 21) and over 28 weeks (RR 1.58, 95% CI 1.10 to 2.27) as well as for painful physical symptoms in depression (RR 1.37, 95% CI 1.19 to 1.59; NNTB 8, 95% CI 5 to 14). There was no effect on central neuropathic pain in a single, small, high quality trial. In all conditions, adverse events were common in both treatment and placebo arms but more common in the treatment arm, with a dose-dependent effect. Most adverse effects were minor, but 12.6% of participants stopped the drug due to adverse effects. Serious adverse events were rare. Authors' conclusions There is adequate amounts of moderate quality evidence from eight studies performed by the manufacturers of duloxetine that doses of 60 mg and 120 mg daily are efficacious for treating pain in diabetic peripheral neuropathy but lower daily doses are not. Further trials are not required. In fibromyalgia, there is lower quality evidence that duloxetine is effective at similar doses to those used in diabetic peripheral neuropathy and with a similar magnitude of effect. The effect in fibromyalgia may be achieved through a greater improvement in mental symptoms than in somatic physical pain. There is low to moderate quality evidence that pain relief is also achieved in pain associated with depressive symptoms, but the NNTB of 8 in fibromyalgia and depression is not an indication of substantial efficacy. More trials (preferably independent investigator led studies) in these indications are required to reach an optimal information size to make convincing determinations of efficacy. Minor side effects are common and more common with duloxetine 60 mg and particularly with 120 mg daily, than 20 mg daily, but serious side effects are rare. Improved direct comparisons of duloxetine with other antidepressants and with other drugs, such as pregabalin, that have already been shown to be efficacious in neuropathic pain would be appropriate. Unbiased economic comparisons would further help decision making, but no high quality study includes economic data.

Rosuvastatin for Sepsis-Associated Acute Respiratory Distress Syndrome

Abstract: Background In the acute respiratory distress syndrome (ARDS), inflammation in the lungs and other organs can cause life-threatening organ failure. Inhibitors of 3-hydroxy3-methylglutaryl coenzyme A reductase (statins) can modulate inflammatory responses. Previous observational studies suggested that statins improved clinical outcomes in patients with sepsis. We hypothesized that rosuvastatin therapy would improve clinical outcomes in critically ill patients with sepsis-associated ARDS. Methods We conducted a multicenter trial in which patients with sepsis-associated ARDS were randomly assigned to receive either enteral rosuvastatin or placebo in a doubleblind manner. The primary outcome was mortality before hospital discharge home or until study day 60 if the patient was still in a health care facility. Secondary outcomes included the number of ventilator-free days (days that patients were alive and breathing spontaneously) to day 28 and organ-failure–free days to day 14. Results The study was stopped because of futility after 745 of an estimated 1000 patients had been enrolled. There was no significant difference between study groups in 60-day in-hospital mortality (28.5% with rosuvastatin and 24.9% with placebo, P = 0 .21) or in mean (±SD) ventilator-free days (15.1±10.8 with rosuvastatin and 15.1±11.0 with placebo, P = 0 .96). The groups were well matched with respect to demographic and key physiological variables. Rosuvastatin therapy, as compared with placebo, was assoc iated with fewer days free of renal failure to day 14 (10.1±5.3 vs. 11.0±4.7, P = 0 .01) and fewer days free of hepatic failure to day 14 (10.8±5.0 vs. 11.8±4.3, P = 0 .003). Rosuvas tatin was not associated with an increased incidence of serum creatine kinase levels that were more than 10 times the upper limit of the normal range. Conclusions Rosuvastatin therapy did not improve clinical outcomes in patients with sepsis a ssociated ARDS and may have contributed to hepatic and renal organ dysfunction. (Funded by the National Heart, Lung, and Blood Institute and the Investigator-Sponsored Study Program of AstraZeneca; ClinicalTrials.gov number, NCT00979121.)

Physical exercise intervention in depressive disorders: Meta-analysis and systematic review

Abstract: Previous meta-analyses investigating the effect of exercise on depression have included trials where the control condition has been categorized as placebo despite the fact that this particular placebo intervention (e.g., meditation, relaxation) has been recognized as having an antidepressant effect. Because meditation and mindfulness-based interventions are associated with depression reduction, it is impossible to separate the effect of the physical exercise from the meditation-related parts. The present study determined the efficacy of exercise in reducing symptoms of depression compared with no treatment, placebo conditions or usual care among clinically defined depressed adults. Of 89 retrieved studies, 15 passed the inclusion criteria of which 13 studies presented sufficient information for calculating effect sizes. The main result showed a significant large overall effect favoring exercise intervention. The effect size was even larger when only trials that had used no treatment or placebo conditions were analyzed. Nevertheless, effect size was reduced to a moderate level when only studies with high methodological quality were included in the analysis. Exercise may be recommended for people with mild and moderate depression who are willing, motivated, and physically healthy enough to engage in such a program.

Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments.

Abstract: Objective To describe the potential benefits and harms of oseltamivir by reviewing all clinical study reports (or similar document when no clinical study report exists) of randomised placebo controlled trials and regulatory comments ("regulatory information"). Design Systematic review of regulatory information. Data sources Clinical study reports, trial registries, electronic databases, regulatory archives, and correspondence with manufacturers. Eligibility criteria for selecting studies Randomised placebo controlled trials on adults and children who had confirmed or suspected exposure to natural influenza. Main outcome measures Time to first alleviation of symptoms, influenza outcomes, complications, admissions to hospital, and adverse events in the intention to treat population. Results From the European Medicines Agency and Roche, we obtained clinical study reports for 83 trials. We included 23 trials in stage 1 (reliability and completeness screen) and 20 in stage 2 (formal analysis). In treatment trials on adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval 8.4 to 25.1 hours, P<0.001). There was no effect in children with asthma, but there was an effect in otherwise healthy children (mean difference 29 hours, 95% confidence interval 12 to 47 hours, P=0.001). In treatment trials there was no difference in admissions to hospital in adults (risk difference 0.15%, 95% confidence interval -0.91% to 0.78%, P=0.84) and sparse data in children and for prophylaxis. In adult treatment trials, oseltamivir reduced investigator mediated unverified pneumonia (risk difference 1.00%, 0.22% to 1.49%; number needed to treat to benefit (NNTB) 100, 95% confidence interval 67 to 451). The effect was not statistically significant in the five trials that used a more detailed diagnostic form for "pneumonia," and no clinical study reports reported laboratory or diagnostic confirmation of "pneumonia." The effect on unverified pneumonia in children and for prophylaxis was not significant. There was no significant reduction in risk of unverified bronchitis, otitis media, sinusitis, or any complication classified as serious or that led to study withdrawal. 14 of 20 trials prompted participants to self report all secondary illnesses to an investigator. Oseltamivir in the treatment of adults increased the risk of nausea (risk difference 3.66%, 0.90% to 7.39%; number needed to treat to harm (NNTH) 28, 95% confidence interval 14 to 112) and vomiting (4.56%, 2.39% to 7.58%; 22, 14 to 42). In treatment of children, oseltamivir induced vomiting (5.34%, 1.75% to 10.29%; 19, 10 to 57). In prophylaxis trials, oseltamivir reduced symptomatic influenza in participants by 55% (3.05%, 1.83% to 3.88%; NNTB 33, 26 to 55) and households (13.6%, 9.52% to 15.47%; NNTB 7, 6 to 11) based on one study, but there was no significant effect on.